Clinical trial NCT05898672
Conditions: Pharmacokinetics Healthy Volunteers
Keywords: Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nirmatrelvir Paxlovid Rosuvastatin
Sponsor: Pfizer
Start date: 2023-06-09; Completion date: 2023-08-10
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to learn about the effect of the study medicine (called nirmatrelvir/ritonavir) on the pharmacokinetics of the medicine rosuvastatin in healthy volunteers. Pharmacokinetics helps us understand how the drug is changed and eliminated from your body after you take it.

This study is seeking participants who:

* are male and female participants who are overtly healthy
* are 18 years of age or older
* have a Body mass Index (BMI) of 16-32 kg/m2 and total body weight \>50 kg (110 lb).

All participants in this study will receive nirmatrelvir/ritonavir, a standard treatment for mild-to-moderate COVID-19. All participants will also receive rosuvastatin.

Nirmatrelvir/ritonavir will be given by mouth at the study clinic 2 times a day. Rosuvastatin will be given by mouth at the study clinic once (as a single dose).

We will compare participant experiences to help us determine the effect of nirmatrelvir/ritonavir on the pharmacokinetics of rosuvastatin.

Participants will take part in this study for approximately 11 weeks. During this time, they will have 10 days at the study clinic and 1 follow-up phone call. Blood samples will be collected during participants' time at the study clinic.

Detailed description:

Arms: arm 1: Rosuvastatin tablets arm 2: Rosuvastatin + nirmatrelvir/ritonavir tablets
Interventions: intervention 1: Rosuvastatin intervention 2: Nirmatrelvir/ritonavir
Intervention descriptions: intervention 1: Single oral dose of rosuvastatin tablets intervention 2: Twice daily oral doses of nirmatrelvir/ritonavir tablets

Protocol documents:
Prot_000.pdf: 
Nirmatrelvir (PF-07321332)
Protocol C4671052
Final Protocol Amendment 1, 10 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
Page 1
Title Page
A PHASE 1, RANDOMIZED, FIXED SEQUENCE, MULTIPLE-DOSE, 
OPEN-LABEL STUDY TO ESTIMATE THE EFFECT OF NIRMATRELVIR 
(PF-07321332)/RITONAVIR ON ROSUVASTATIN PHARMACOKINETICS IN 
HEALTHY ADULT PARTICIPANTS
Study Intervention Number:
PF-07321332
Study Intervention Name:
Nirmatrelvir
US IND Number:
153517
EUCT Number:
2023-503570-20-00
ClinicalTrials.gov ID:
Not Available
Pediatric Investigational Plan Number:
Not Applicable
Protocol Number:
C4671052
Phase:
1
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Study to Learn About the Study Medicine Called Nirmatrelvir/Ritonavir 
in People Who are Healthy Volunteers Co-administered the Medicine Rosuvastatin
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Protocol C4671052
Final Protocol Amendment 1, 10 May 2023
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Amendment 1
10 May 2023
Original protocol
03 April 2023
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol administrative 
change letter(s).
Protocol Amendment Summary of Changes Table
Amendment 1 (10 May 2023)
Overall Rationale for the Amendment: The protocol was amended to include additional 
risks and risk mitigation measures for ritonavir and rosuvastatin dosing, as well as to add 
additional safety laboratory testing and physical examinations.
Description of Change
Brief Rationale
Section # and Name
Addition of haematological 
abnormalities as a risk of 
ritonavir dosing, along with 
risk mitigation measures.
Risk and risk mitigation 
measures added to align 
with ritonavir prescribing 
information (Norvir®
SmPC).
Section 2.3.1 Risk 
Assessment
Addition of severe 
cutaneous adverse reactions
as a risk of rosuvastatin 
dosing, along with risk 
mitigation measures.
Risk and risk mitigation 
added to align with 
rosuvastatin prescribing 
information (Crestor®
SmPC).
Section 2.3.1 Risk 
Assessment
Safety laboratory testing 
added on Day 3, Period 1; 
Day 5, Period 1; and Day 3, 
Period 2.
Additional safety laboratory 
testing timepoints were 
included as additional risk 
mitigation to monitor for
haematological 
abnormalities following 
ritonavir dosing as well as 
liver enzyme abnormalities 
and skeletal muscle effects 
following rosuvastatin 
dosing. Day 5, Period 1 
timepoint added as a
mitigation prior to initiating 
Period 2 dosing.
Sections 1.3 Schedule of 
Activities, Section 2.3.1 
Risk Assessment and 
Section 8.1 Administrative 
and Baseline Procedures
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Protocol C4671052
Final Protocol Amendment 1, 10 May 2023
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Description of Change
Brief Rationale
Section # and Name
Brief physical examinations 
added on Day 5, Period 1; 
Day 2, Period 2; and Day 5, 
Period 2.
Additional physical 
examinations were included 
as additional risk mitigation 
to monitor for rashes 
following ritonavir dosing 
as well as skeletal muscle 
effects and severe cutaneous 
adverse reactions following 
rosuvastatin dosing. Day 5, 
Period 1 timepoint added as 
a mitigation prior to 
initiating Period 2 dosing.
Sections 1.3 Schedule of 
Activities and Section 2.3.1
Risk Assessment
Skin and skeletal muscle 
assessment added to brief 
physical exams.
To monitor for rashes and 
skeletal muscle effects 
following ritonavir and 
rosuvastatin dosing.
Section 8.3.1 Physical 
Examinations
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Protocol C4671052
Final Protocol Amendment 1, 10 May 2023
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES ...................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities .............................................................................................17
2. INTRODUCTION ...............................................................................................................21
2.1. Study Rationale .......................................................................................................21
2.2. Background .............................................................................................................21
2.2.1. Nonclinical Pharmacology..........................................................................21
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................21
2.2.3. Nonclinical Safety ......................................................................................22
2.2.4. Clinical Overview.......................................................................................22
2.2.4.1. Safety Overview........................................................................23
2.2.4.2. Summary of Nirmatrelvir/Ritonavir Pharmacokinetics in 
Human ...............................................................................................24
2.3. Benefit/Risk Assessment.........................................................................................25
2.3.1. Risk Assessment.........................................................................................26
2.3.2. Benefit Assessment.....................................................................................30
2.3.3. Overall Benefit/Risk Conclusion................................................................30
3. OBJECTIVES AND ENDPOINTS.....................................................................................30
4. STUDY DESIGN.................................................................................................................30
4.1. Overall Design.........................................................................................................30
4.2. Scientific Rationale for Study Design.....................................................................32
4.2.1. Choice of Contraception/Barrier Requirements .........................................34
4.3. Justification for Dose ..............................................................................................34
4.4. End of Study Definition ..........................................................................................35
5. STUDY POPULATION......................................................................................................35
5.1. Inclusion Criteria.....................................................................................................36
5.2. Exclusion Criteria....................................................................................................36
5.3. Lifestyle Considerations..........................................................................................39
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5.3.1. Contraception..............................................................................................39
5.3.2. Meals and Dietary Restrictions...................................................................39
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................40
5.3.4. Activity .......................................................................................................40
5.4. Screen Failures ........................................................................................................40
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................40
6.1. Study Intervention(s) Administered........................................................................41
6.1.1. Administration............................................................................................42
6.2. Preparation, Handling, Storage, and Accountability...............................................43
6.2.1. Preparation and Dispensing........................................................................44
6.3. Assignment to Study Intervention...........................................................................44
6.4. Blinding...................................................................................................................44
6.4.1. Blinding of Participants..............................................................................44
6.4.2. Blinding of Site Personnel..........................................................................44
6.4.3. Blinding of the Sponsor..............................................................................45
6.5. Study Intervention Compliance...............................................................................45
6.6. Dose Modification...................................................................................................45
6.7. Continued Access to Study Intervention After the End of the Study......................45
6.8. Treatment of Overdose............................................................................................45
6.9. Prior and Concomitant Therapy..............................................................................46
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................46
7.1. Discontinuation of Study Intervention ....................................................................46
7.1.1. Potential Cases of Acute Kidney Injury .....................................................47
7.1.2. ECG Changes..............................................................................................48
7.1.3. Stopping Rules............................................................................................48
7.2. Participant Discontinuation/Withdrawal From the Study.......................................48
7.2.1. Withdrawal of Consent...............................................................................49
7.3. Lost to Follow-Up ...................................................................................................49
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................50
8.1. Administrative and Baseline Procedures.................................................................50
8.2. Efficacy Assessments..............................................................................................51
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8.3. Safety Assessments .................................................................................................51
8.3.1. Physical Examinations................................................................................51
8.3.2. Vital Signs ..................................................................................................52
8.3.2.1. Blood Pressure and Pulse Rate..................................................52
8.3.2.2. Temperature ..............................................................................52
8.3.3. Electrocardiograms.....................................................................................53
8.3.4. Clinical Safety Laboratory Assessments ....................................................53
8.3.5. COVID-19 Specific Assessments...............................................................54
8.3.6. Pregnancy Testing ......................................................................................54
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................54
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......55
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................55
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................56
8.4.2. Method of Detecting AEs and SAEs ..........................................................56
8.4.3. Follow-Up of AEs and SAEs......................................................................56
8.4.4. Regulatory Reporting Requirements for SAEs...........................................56
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................57
8.4.5.1. Exposure During Pregnancy......................................................57
8.4.5.2. Exposure During Breastfeeding ................................................59
8.4.5.3. Occupational Exposure .............................................................59
8.4.6. Cardiovascular and Death Events...............................................................59
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................59
8.4.8. Adverse Events of Special Interest.............................................................59
8.4.8.1. Lack of Efficacy........................................................................59
8.4.9. Medical Device Deficiencies......................................................................60
8.4.10. Medication Errors.....................................................................................60
8.5. Pharmacokinetics ....................................................................................................60
8.6. Genetics...................................................................................................................61
8.6.1. Specified Genetics ......................................................................................61
8.6.2. Retained Research Samples for Genetics ...................................................61
8.7. Biomarkers ..............................................................................................................61
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8.7.1. Pharmacodynamic Biomarkers...................................................................62
8.8. Immunogenicity Assessments.................................................................................62
8.9. Health Economics ...................................................................................................63
9. STATISTICAL CONSIDERATIONS ................................................................................63
9.1. Statistical Hypotheses .............................................................................................63
9.2. Analysis Sets ...........................................................................................................63
9.3. Statistical Analyses .................................................................................................63
9.3.1. General Considerations...............................................................................63
9.3.2. Primary Endpoint(s) Analysis.....................................................................63
9.3.2.1. Definition of Endpoint(s) ..........................................................64
9.3.3. Other Safety Analyses ................................................................................65
9.3.4. Other Analyses............................................................................................65
9.3.4.1. Biomarker Assessment..............................................................65
9.4. Interim Analyses .....................................................................................................65
9.5. Sample Size Determination.....................................................................................66
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................67
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............67
10.1.1. Regulatory and Ethical Considerations ....................................................67
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................67
10.1.2. Financial Disclosure .................................................................................68
10.1.3. Informed Consent Process ........................................................................68
10.1.4. Data Protection .........................................................................................69
10.1.5. Committees Structure ...............................................................................69
10.1.5.1. Data Monitoring Committee ...................................................69
10.1.6. Dissemination of Clinical Study Data ......................................................69
10.1.7. Data Quality Assurance ............................................................................70
10.1.8. Source Documents....................................................................................72
10.1.9. Study and Site Start and Closure ..............................................................72
10.1.10. Publication Policy...................................................................................73
10.1.11. Sponsor’s Medically Qualified Individual..............................................74
10.2. Appendix 2: Clinical Laboratory Tests .................................................................75
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................77
10.3.1. Definition of AE .......................................................................................77
10.3.2. Definition of an SAE ................................................................................78
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................79
10.3.4. Reporting of SAEs....................................................................................83
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................85
10.4.1. Male Participant Reproductive Inclusion Criteria....................................85
10.4.2. Female Participant Reproductive Inclusion Criteria.................................85
10.4.3. Woman of Childbearing Potential ............................................................86
10.4.4. Contraception Methods.............................................................................87
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments .......89
10.6. Appendix 6: Kidney Safety: Monitoring Guidelines ............................................91
10.6.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................91
10.6.2. Age-Specific Kidney Function Calculation Recommendations...............91
10.6.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................91
10.6.3. Kidney Function Calculation Tools..........................................................92
10.6.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................92
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................93
10.8. Appendix 8: Abbreviations ...................................................................................95
11. REFERENCE.....................................................................................................................99
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LIST OF TABLES
Table 1.
Study Schedule of Assessment.................................................................17
Table 2.
Rosuvastatin Pharmacokinetic Sampling Times ......................................20
Table 3.
Treatment Sequence..................................................................................31
Table 4.
Assessment of Risk for in Vivo DDIs Between Nirmatrelvir and 
Co-administered Substrates of OATP1B1 Transporter, Based on the 
2012 EMA Drug Interactions Guideline...................................................33
Table 5.
Changes in CP-1 and Statin AUC ratios...................................................62
Table 6.
Plasma Rosuvastatin PK Parameters Definitions .....................................64
Table 7.
Expected Width of 90% Confidence Interval for Different Possible 
Estimated Effects and Parameters of Interest...........................................66
Table 8.
Protocol-Required Laboratory Assessments.............................................75
LIST OF FIGURES
Figure 1.
Study Schema ...........................................................................................16
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1. PROTOCOL SUMMARY 
1.1. Synopsis
This is a Phase 1, randomized, fixed sequence, multiple-dose, open-label study of the effect 
of nirmatrelvir (PF-07321332)/ritonavir on rosuvastatin pharmacokinetics (PK) in healthy 
adult participants. The study will also assess the safety and tolerability of a single dose of 
rosuvastatin when coadministered with nirmatrelvir/ritonavir.
Protocol Title: A Phase 1, Randomized, Fixed Sequence, Multiple-Dose, Open-Label Study 
to Estimate the Effect of Nirmatrelvir (PF-07321332)/Ritonavir on Rosuvastatin 
Pharmacokinetics in Healthy Adult Participants
Brief Title: A Study to Learn About the Study Medicine Called Nirmatrelvir/Ritonavir in 
People Who are Healthy Volunteers Co-administered the Medicine Rosuvastatin
Regulatory Agency Identification Number(s):
US IND Number:
153517
EUCT Number:
2023-503570-20-00
ClinicalTrials.gov ID:
Not available
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C4671052
Phase:
1
Rationale:
Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) main protease (Mpro) that was developed as an oral treatment 
of coronavirus disease 2019 (COVID-19). Ritonavir is a strong cytochrome P450 (CYP)3A4 
inhibitor being used to inhibit the metabolism of nirmatrelvir (PF-07321332) in order to 
increase plasma concentrations of nirmatrelvir to values that are efficacious. The clinical 
development program for nirmatrelvir/ritonavir includes 16 completed clinical studies: 
11 Phase 1 studies in healthy participants (C4671001, C4671008, C4671012, C4671013, 
C4671014, C4671015, C4671016, C4671019, C4671023, C4671024, and C4671036), one 
Phase 1 study in renal impairment participants (C4671011), one Phase 1 study in hepatic 
impairment participants (C4671010) and 3 Phase 2/3 pivotal studies in COVID-19 patients 
(C4671002, C4671005, and C4671006).
Both nirmatrelvir and ritonavir have the potential to inhibit OATP1B1. Rosuvastatin is a 
well-known sensitive substrate of OATP1B1 and is likely to be a concomitant medication in 
patients who have COVID-19 and are prescribed nirmatrelvir/ritonavir. Therefore, this study 
will assess the impact of nirmatrelvir/ritonavir on the pharmacokinetics of rosuvastatin.
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Objectives and Endpoints:
Objectives
Endpoints
Primary:
Primary:

To assess the effect of multiple doses of 
nirmatrelvir/ritonavir on the plasma pharmacokinetics of 
a single, oral dose of rosuvastatin in healthy participants.
AUCinf and Cmax of rosuvastatin.
Secondary:
Secondary:

To further characterize the plasma pharmacokinetics of a 
single, oral dose of rosuvastatin administered with 
nirmatrelvir/ritonavir.

To evaluate the safety and tolerability of a single oral 
dose of rosuvastatin when coadministered with 
nirmatrelvir/ritonavir.
AUClast, Tmax, t½, CL/F, and Vz/F of 
rosuvastatin.
Vital signs, laboratory tests and adverse 
events.
Overall Design:
This is a Phase 1, randomized, fixed sequence, multiple-dose, open-label study of the effect 
of nirmatrelvir/ritonavir on rosuvastatin PK in healthy adult participants. Participants will 
receive 2 treatments across 2 periods, as described below:
Sequence
Period 1
Washout
Period 2
Sequence 1 (N = 12)
Treatment A
At least 5 days between the 
2 rosuvastatin dosing events
Treatment B
Abbreviation: N = number of enrolled participants.

Treatment A (rosuvastatin, Reference): Single oral administration of rosuvastatin 10 mg 
tablet on Day 1 in the morning (AM dose).

Treatment B (rosuvastatin + nirmatrelvir/ritonavir, Test): nirmatrelvir/ritonavir 300 mg 
(2×150 mg)/100 mg tablets q12h (BID) for 2 days (Day 1 morning [AM] and evening 
[PM] and Day 2 morning [AM], 3 doses total) with a single oral administration of 
rosuvastatin 10 mg tablet on Day 2 in the morning (AM dose). Nirmatrelvir and ritonavir 
will be dosed within no more than 5 minutes of each other. Rosuvastatin single dose will 
be dosed within 5 minutes after the Day 2 morning (AM) nirmatrelvir/ritonavir dose.
The expected duration of participation from Screening to the follow-up telephone contact 
will be approximately 11 weeks.
A total of approximately 12 healthy male and/or female participants will be enrolled in the 
study. Participants who discontinue from the study may be replaced at the sponsor’s 
discretion.
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Participants will report to the clinical research unit (CRU) the day prior to Day 1 dosing (ie,
Day -1) in Period 1. Participants will remain in the CRU for a total of 11 days and 10 nights
(including Period 1 and Period 2). To adequately remove any drug effects of rosuvastatin 
from Period 1 to Period 2, there will be a minimum 5-day washout period between the 
2 rosuvastatin dosing events. The total rosuvastatin PK will then be assessed over 72 hours.
If a participant has any clinically significant, study related abnormalities at the conclusion of 
a scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the CRU 
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up.
A safety follow-up call will be made to participants approximately 28 to 35 days from 
administration of the final dose of study intervention.
Number of Participants:
Approximately 12 participants will be enrolled in the study.
Note: “Enrolled” means a participant’s, or their legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening.
Study Population:
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:
1. Male and female participants aged 18 years (or the minimum age to consent in 
accordance with local regulations) or older at Screening who are overtly healthy as 
determined by medical evaluation including medical history, physical examination, 
laboratory tests, vital signs, and standard 12-lead electrocardiogram (ECG).
2. Participants who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, lifestyle considerations, and other study procedures.
3. Female participants must have a negative pregnancy test.
4. Body mass index (BMI) of 16-32 kg/m2 and a total body weight >50 kg (110 lb).
5. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent document (ICD) and in this 
protocol.
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Exclusion Criteria
Participants with any of the following characteristics/conditions will be excluded:
1. Positive test result for SARS-CoV-2 infection on Day -1 or who have received a 
COVID-19 vaccine within 7 days before screening or admission, or who are to be 
vaccinated with a COVID-19 vaccine at any time during the study confinement.
2. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease 
(including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the 
time of dosing).

Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).

History of human immunodeficiency virus (HIV) infection, hepatitis B, or 
hepatitis C; positive testing for HIV, hepatitis B surface antigen (HBsAg), or hepatitis 
C antibody (HCVAb). Hepatitis B vaccination is allowed.
3. Clinically relevant abnormalities requiring treatment (eg, acute myocardial infarction, 
unstable ischemic conditions, evidence of ventricular dysfunction, serious tachy- or 
brady-arrhythmias) or indicating serious underlying heart disease (eg, prolonged PR 
interval, cardiomyopathy, heart failure greater than New York Heart Association 
Functioncal Classification 1 (NYHA 1), underlying structural heart disease, Wolff 
Parkinson-White syndrome).
4. Any medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality or other conditions that may increase 
the risk of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
5. Participants, who according to the product label for rosuvastatin, would be at increased 
risk if dosed with rosuvastatin.
Study Arms and Duration:
Study Intervention(s)
Intervention Name
PF-07321332 
(nirmatrelvir) tablets
Ritonavir tablets
Rosuvastatin tablets
Use
Test
Test
Reference, Test
IMP or NIMP/AxMP
IMP
NIMP/AxMP
NIMP/AxMP
Dose Formulation
Tablet
Tablet
Tablet
Unit Dose Strength(s)
150 mg
100 mg
10 mg
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Study Intervention(s)
Route of 
Administration
Oral
Oral
Oral
Study Arm/Period(s)
Arm/Period Title
Treatment A (rosuvastatin, 
Reference)
Treatment B (rosuvastatin + 
nirmatrelvir/ritonavir, Test)
Arm/Period
Description
Single oral dose of rosuvastatin 
10 mg tablet on Day 1 in the 
morning (AM dose).
Nirmatrelvir/ritonavir 300 mg (2 x 150 
mg)/100 mg tablets q12h (BID) for 2 days
(Day 1 morning [AM] and evening [PM] and 
Day 2 morning [AM], 3 doses total) with a 
single oral dose of rosuvastatin 10 mg tablet 
on Day 2 in the morning (AM dose). 
Nirmatrelvir and ritonavir will be dosed 
within no more than 5 minutes of each other. 
Rosuvastatin single dose will be dosed within 
5 minutes after the first Day 2 morning (AM)
nirmatrelvir/ritonavir dose.
Statistical Methods:
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effect model with treatment as a fixed effect and participant as a random effect. 
Estimates of the adjusted mean differences (Test-Reference) and corresponding 
90% confidence intervals (CIs) will be obtained from the model. The adjusted mean 
differences and 90% CIs for the differences will be exponentiated to provide estimates of the 
ratio of adjusted geometric means (Test/Reference) and 90% CI for the ratios. Treatment A 
(rosuvastatin) will be the Reference treatment while Treatment B (rosuvastatin + 
nirmatrelvir/ritonavir) will be the Test treatment.
The PK concentration analysis set is defined as all participants who take at least 1 dose of 
study intervention and in whom at least 1 concentration value is reported. The PK parameter 
analysis set is defined as all participants who take at least 1 dose of study intervention and in 
whom at least 1 of the PK parameters of primary interest are reported. Plasma PK parameters 
of rosuvastatin will be derived (as data permits) from the concentration-time data using 
standard noncompartmental methods. Actual PK sampling times will be used in the 
derivation of rosuvastatin PK parameters when available, otherwise nominal times will be 
used.
PK parameters, including plasma AUCinf, AUClast, Cmax, Tmax , t½, CL/F, and Vz/F of 
rosuvastatin will be summarized descriptively by treatment. For AUCinf, AUClast and Cmax, a 
listing of the individual participant ratios (Test/Reference) will be provided. Box and whisker 
plots for AUCinf, AUClast and Cmax will be plotted by treatment.
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Adverse events (AEs), ECGs, blood pressure (BP), pulse rate, and safety laboratory data will 
be reviewed and summarized on an ongoing basis during the study to evaluate the safety of 
participants. Any clinical laboratory, ECG, BP, and PR abnormalities of potential clinical 
concern will be described. Safety data will be presented in tabular and/or graphical format 
and summarized descriptively, where appropriate.
Ethical Considerations:
Neither nirmatrelvir/ritonavir nor rosuvastatin are expected to provide any clinical benefit to 
healthy participants in this study. This study is designed primarily to further the 
understanding of human PK, metabolism, and elimination of nirmatrelvir/ritonavir.
Based on data from Study C4671001, the clinical safety profile of nirmatrelvir appears to be
acceptable at single doses up to 1500 mg alone and up to 2250 mg administered with 
ritonavir (100 mg at -12h, 0h, 12h), split dosing administration (2250 mg, administered as 
3 doses of 750 mg) at short intervals (approximately 2 hours from the previous dose), and at 
repeated daily doses administered orally for 10 days of up to 500 mg nirmatrelvir q12h with 
100 mg ritonavir q12h.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of nirmatrelvir/ritonavir may be found in the Investigator’s Brochure
(IB), which is the Single Reference Safety Document (SRSD) for this study.
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1.2. Schema
Figure 1.
Study Schema
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 8
Screeninga
Period 1b
Treatment A
Period 2
Treatment B
F/U
Early 
Discontinuation
Days Relative to Day 1
-28 to -2
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5
Day 1 Day 2 Day 3 Day 4 Day 5 28-35 Daysc
Informed consent
X
CRU confinementd
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Medical/medication history (update)e
X
X
Demographyf
X
Physical examinationg
X
X
X
X
X
Safety laboratoryh
X
X
X
X
X
X
X
FSHi
X
Urine drug testingj
X
X
Serology: HBsAg, HBsAb, HBcAb, HCVAb, 
and HIV
X
Pregnancy test (WOCBP only)
X
X
X
X
Contraception checkk
X
X
X
12-lead ECG (triplicate)l
X
X
Vital signs (BP/PR)m
X
X
X
X
X
X
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 8
Screeninga
Period 1b
Treatment A
Period 2
Treatment B
F/U
Early 
Discontinuation
Days Relative to Day 1
-28 to -2
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5
Day 1 Day 2 Day 3 Day 4 Day 5 28-35 Daysc
COVID-19 testingn
X
COVID-19 temperature checkn
X
Nirmatrelvir/ritonavir administrationo
X
X
Rosuvastatin administrationp
X
X
PK blood sampling for rosuvastatinq
X
X
X
X
X
X
X
X
X
PK blood sampling for nirmatrelvir/ritonavirr
X
Blood sampling for CP-1s
X
X
Serious and non-serious AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant treatment(s)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge from CRUt
X
a.
Screening will be performed within 28 days prior to the first dose of nirmatrelvir/ritonavir.
b.
Participants will report to the CRU the day prior to Day 1 dosing (ie, Day -1) in Period 1. Participants will remain in the CRU for a total of 11 days and 10 nights (including 
Period 1 and Period 2).
c.
Follow-up contact will occur via telephone contact and must occur between 28 to 35 days from administration of the final dose of rosuvastatin.
d.
Participants will be admitted to the CRU on Day -1. Participants will be discharged on Day 5, Period 2 following the final assessments. 
e.
Medical history will include a history of prior illegal drug, alcohol, and tobacco use, as well as blood donation within prior 60 days. Medical history will be recorded at 
Screening and updated on Day -1 of Period 1. 
f.
Demographics will include participant race, ethnicity, age, and gender during the Screening visit. 
g.
A complete physical examination will be performed by trained medical personnel at the investigator site at Screening or Day -1 of Period 1 only (height and weight must be 
obtained at Screening to obtain BMI for eligibility criteria). A brief physical examination will be performed on Day 5 of Period 1, Day 2 of Period 2, and Day 5 of Period 2. 
Additional physical examination(s) may be performed at other time points at the discretion of the investigator.
h.
Safety laboratory assessments including urinalysis, hematology, and chemistry will be performed at the indicated time-points. All the safety laboratory samples must be 
collected following at least a 4-hour fast. Additional safety laboratory assessments may be performed at any time at the discretion of the investigator.
i.
For confirmation of postmenopausal status only in females <60 years old and not using hormonal or HRT only.
j.
Urine drug (mandatory) and alcohol breath test (at discretion of investigator) will be performed at Screening and on Day -1. These tests may be performed at any other time at 
the discretion of the investigator.
k.
The investigator or their designee will inform the participant the need to use highly effective contraception consistently and correctly according to contraception guidelines.
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 8
Screeninga
Period 1b
Treatment A
Period 2
Treatment B
F/U
Early 
Discontinuation
Days Relative to Day 1
-28 to -2
Day -1 Day 1 Day 2 Day 3 Day 4 Day 5
Day 1 Day 2 Day 3 Day 4 Day 5 28-35 Daysc
l.
Triplicate 12-lead ECG readings approximately 2-4 minutes apart will be taken at specified times. All ECG assessments will be made after at least a 5-minute rest in a supine 
position and prior to any blood draws or vital sign measurements.
m.
Single supine BP and PR will be performed following approximately 5 minutes of rest in a supine position. BP and pulse rate assessments will be performed after collection of 
ECGs and prior to collection of blood draws if scheduled at the same time.
n.
COVID-19 assessments will be performed according to local procedures.
o.
Nirmatrelvir/ritonavir will be administered orally, q12h for 2 days (Day 1 morning [AM] and evening [PM] and Day 2 morning [AM], total of 3 doses) in the Treatment B (Test) 
arm only. Nirmatrelvir and ritonavir will be dosed within no more than 5 minutes of each other.
p.
Rosuvastatin will be administered orally as a single dose in both the Treatment A (Reference) and Treatment B (Test) arms. In the Treatment B (Test) arm, rosuvastatin will be 
dosed within 5 minutes after the Day 2 morning (AM) nirmatrelvir/ritonavir dose.
q.
One (approximately 4 mL) blood sample for PK analysis of rosuvastatin will be taken at the following timepoints post-dose in each period: 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 
24, 36, 48, and 72 hours.
r.
One pre-dose blood sample (approximately 4 mL) for PK analysis of nirmatrelvir/ritonavir will be taken prior to the Day 2 morning (AM) dose of nirmatrelvir/ritonavir in the 
Treatment B (Test) arm only to ensure achievement of steady-state trough concentration.
s.
Blood samples (approximately 2 mL) for analysis of CP-1 biomarker will be collected. CP-1 sampling will occur immediately following (i.e., within 5 minutes) the 0, 0.5, 1, 2, 
3, 4, 5, 6, 8, 10, and 12 hours rosuvastatin PK samples during both Treatment A and Treatment B dosing.
t.
Participants will be eligible for discharge in Period 2, Day 5 at the discretion of the investigator following PK sampling at 72 hours post the last dose of rosuvastatin.
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Table 2.
Rosuvastatin Pharmacokinetic Sampling Times
Visit Identifier
Period 1 (Treatment A) and Period 2 (Treatment B)
Notes
Day Relative to 
Rosuvastatin Dose
1
2
3
4
Hours After Dose
0
0.5
1
2
3
4
5
6
8
10
12
16
24
36
48
72
Hour 0 = predose sample collection
Rosuvastatin treatment 
administration
X
Rosuvastatin PK blood sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CP-1 blood sampling
X
X
X
X
X
X
X
X
X
X
X
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2. INTRODUCTION
Nirmatrelvir is a potent and selective inhibitor of the SARS-CoV-2 Mpro that was developed 
for the treatment of COVID-19. Ritonavir is a strong CYP3A4 inhibitor being used to inhibit 
the metabolism of nirmatrelvir in order to increase plasma concentrations of nirmatrelvir to 
values that are efficacious.
2.1. Study Rationale
The purpose of the study is to assess the effect of nirmatrelvir/ritonavir on the plasma PK of 
rosuvastatin, a sensitive OATP1B1 substrate. Both nirmatrelvir and ritonavir have the 
potential to inhibit OATP1B1.1,2 Rosuvastatin is considered a well-known sensitive substrate 
of OATP1B1 and is likely to be a concomitant medication in patients who have COVID-19 
and are prescribed nirmatrelvir/ritonavir. Therefore, this study will assess the impact of 
nirmatrelvir/ritonavir on the pharmacokinetics of rosuvastatin.
2.2. Background
In December 2019, COVID-19 was identified as a new, potentially fatal, respiratory infection 
caused by the novel coronavirus, SARS-CoV-2. The WHO declared COVID-19 a Public 
Health Emergency of International Concern on 30 January 2020 and further characterized the 
disease outbreak as a pandemic on 11 March 2020.2
Nirmatrelvir is an orally bioavailable 3CLpro inhibitor shown to be effective against 
SARS-CoV-2 3CLpro (Ki = 0.00311 µM) in a biochemical enzymatic assay. Nirmatrelvir was
developed as an oral treatment in patients with COVID-19 infection.
Ritonavir is a strong CYP3A4 inhibitor being used to inhibit the metabolism of nirmatrelvir 
in order to increase plasma concentrations of nirmatrelvir to values that are efficacious. 
Ritonavir is not expected to have any pharmacological impact on the SARS-CoV-2 virus and 
its elimination. Ritonavir is being used only as a PK boosting agent.
The clinical development program for nirmatrelvir/ritonavir includes 16 completed clinical 
studies: 11 Phase 1 studies in healthy participants (C4671001, C4671008, C4671012, 
C4671013, C4671014, C4671015, C4671016, C4671019, C4671023, C4671024, and 
C4671036), one Phase 1 study in renal impairment participants (C4671011), one Phase 1 
study in hepatic impairment participants (C4671010) and three Phase 2/3 pivotal study in 
COVID-19 patients (C4671002, C4671005, and C4671006).
2.2.1. Nonclinical Pharmacology
Details of the nonclinical pharmacology of nirmatrelvir/ritonavir can be found in the current 
IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Hepatic CYP3A enzymes were identified as the main pathway for clearance of nirmatrelvir 
in vitro in liver microsomes (mouse, rat, hamster, rabbit, monkey, and human), hepatocytes 
(rat, monkey, and human), and in vivo in rat and monkey after repeat oral dosing. In a 
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reaction phenotyping study using human liver microsomes in the presence of selective CYP 
inhibitors, CYP3A4 was predicted to be the major contributor (fm = 0.99) to the in vitro 
oxidative metabolism of nirmatrelvir. No significant CYP3A5 contribution is expected to the 
metabolism of nirmatrelvir.
Due to the predominant role of CYP3A4 in the metabolic clearance of nirmatrelvir, ritonavir 
(a CYP3A4 inhibitor) is administered in clinical use in order to increase the plasma 
concentrations of nirmatrelvir. Upon coadministration with ritonavir, the primary clearance 
mechanism of nirmatrelvir is renal elimination of unchanged drug.
Nirmatrelvir has low potential to inhibit a majority of various efflux and uptake transporters 
as investigated using stably transfected HEK293 cells or vesicle-based systems. At the 
proposed therapeutic dose, there is a potential for pharmacokinetic interactions arising from
the inhibition of MDR1 (P-gp) and OATP1B1 by nirmatrelvir. Additionally, ritonavir has the 
potential to inhibit OATP1B1 (see Section 4.2). Additional information of the nonclinical PK
and metabolism of nirmatrelvir and nirmatrelvir/ritonavir is available in the current IB.
2.2.3. Nonclinical Safety
There were no adverse findings observed in repeat-dose toxicity studies in rats and monkeys 
up to 2 weeks duration and the NOAELs were the highest dose administered (1000 mg/kg 
and 600 mg/kg in the rat and monkey studies, respectively). Nirmatrelvir-related nonadverse, 
test article-related clinical findings included sporadic occurrence of emesis with slight body 
weight decreases in monkeys in the 1-month study. In rats, monitorable and reversible 
clinical pathology findings included those possibly suggestive of low-grade inflammation or 
alterations in the coagulation pathways without clinical or microscopic correlates. In 
monkeys, monitorable and reversible clinical pathology findings included increase in ALT 
and/or AST and increase in fibrinogen at the high dose in 1-month study without clinical or 
microscopic correlates. In rats administered 1000 mg/kg/day, lower mean absolute and 
relative heart weights (females) and higher mean liver weights (both sexes) were observed 
relative to controls. The lower heart weights had no microscopic correlates and were fully 
reversed at the end of the 2-week recovery period. Higher liver weights correlated with 
reversible, nonadverse microscopic findings of minimal to mild severity in the liver and 
thyroid gland consistent with adaptive changes related to microsomal enzyme induction.
Nirmatrelvir was not mutagenic or clastogenic in in vitro genetic toxicity studies and was 
negative in the in vivo rat micronucleus assay incorporated into the GLP repeat-dose rat 
toxicity study.
The nonclinical studies performed adequately support the oral administration of nirmatrelvir 
in the clinic for up to 14 days.
Further details of the nonclinical safety program are provided in the current IB.
2.2.4. Clinical Overview
Safety, tolerability and PK of nirmatrelvir has been assessed in studies in healthy adult 
participants (C4671001, C4671008, C4671013, C4671014, C4671015, C4671016, 
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C4671019, C4671023, C4671024, and C4671036), as well as in renal impairment 
participants (C4671011) and hepatic impairment participants (C4671010). The relative 
bioavailability and food effect were evaluated in two phase 1 studies (C4671001 and 
C4671019) in healthy participants. Efficacy and safety of nirmatrelvir were evaluated in 
interventional Phase 2/3 Studies (C4671002, C4671005, C4671006). 
Included in this Clinical Overview are summaries of the results of Study C4671001 and 
C4671005.
Study C4671001 was a 5-part study consisting of SAD (PART-1), MAD (PART-2), relative 
bioavailability/food effect (PART-3), metabolism and excretion study (PART-4) and 
supratherapeutic exposure cohort (PART-5). PART-1 and -2 are randomized, double-blind, 
sponsor-open, and placebo-controlled to evaluate safety, tolerability, and PK of single and 
multiple escalating oral doses of nirmatrelvir, respectively. PART-3 was randomized and 
open-label to evaluate relative bioavailability and food effect of an oral tablet formulation. 
PART-4 was an open-label, nonrandomized, single-period to evaluate the metabolism and 
excretion of nirmatrelvir. PART-5 was a double-blind, sponsor-open, randomized, crossover 
study to evaluate safety and tolerability at supratherapeutic exposures. 
C4671005 evaluated the efficacy and safety of nirmatrelvir in an interventional Phase 2/3 
Study (C4671005). C4671005 was a Phase 2/3 randomized, placebo-controlled trial in 
nonhospitalized adult participants with a laboratory-confirmed diagnosis of SARS-CoV-2 
infection.
2.2.4.1. Safety Overview
In the completed Phase 1 studies in healthy participants and Phase 2/3 study in participants 
with a laboratory-confirmed diagnosis of SARS-CoV-2 infection, nirmatrelvir/ritonavir was 
generally safe and well tolerated.
Safety data from Study C4671001 indicate that nirmatrelvir was safe and well tolerated in 
healthy adult participants at all the exposures tested including supratherapeutic exposure. 
Current evidence indicates that the clinical safety profile of nirmatrelvir is acceptable at 
single doses up to a 2250 mg dose administered as 3 split doses of 750 mg administered with 
ritonavir, and at repeated daily doses administered orally for 10 days of up to 500 mg 
nirmatrelvir BID with 100 mg ritonavir BID. In all 5-parts of the study, there were no deaths, 
severe AEs, or SAEs. nirmatrelvir alone or nirmatrelvir/ritonavir was generally safe and well 
tolerated in healthy participants in all parts including SAD, MAD, and SE cohorts. No 
notable safety findings were observed. All TEAEs were mild in severity, except for one AE 
which was moderate in severity, and not considered treatment related. Overall, there were no 
clinically meaningful laboratory changes, no clinically significant findings in vital sign 
measurements or 12-lead ECG assessments throughout this study. The safety data, including 
AEs, laboratory abnormalities, vital signs, and 12-lead ECGs indicate that nirmatrelvir has an 
acceptable safety and tolerability profile in healthy adult participants.
C4671005 is a Phase 2/3 randomized, placebo-controlled trial in nonhospitalized adult 
participants with a laboratory-confirmed diagnosis of SARS-CoV-2 infection. A total of 
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2224 symptomatic adult participants 18 years of age and older at high risk of developing 
severe disease received at least 1 dose of either nirmatrelvir/ritonavir (n=1,109) or placebo 
(n=1,115). Adverse events (all grades regardless of causality) in the nirmatrelvir/ritonavir
group (≥1%) that occurred at a greater frequency (≥5 participant difference) than in the 
placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), 
hypertension (1% and <1%), and myalgia (1% and <1%).
Further details on the clinical safety information with nirmatrelvir are provided in the current 
IB.
2.2.4.2. Summary of Nirmatrelvir/Ritonavir Pharmacokinetics in Human
Study 1001 - FIH
Single dose PK data from Study C4671001 at nirmatrelvir doses of 150 mg, 500 mg, and 
1500 mg alone and at 250 mg and 750 mg with ritonavir 100 mg (dosed at -12, 0, and 
12 hours) show that nirmatrelvir was absorbed rapidly with median Tmax of 1 hour or less 
when administered alone and 2.75 hours or less when administered with ritonavir. Since 
nirmatrelvir is primarily metabolized by CYP3A4 and ritonavir is a CYP3A4 inhibitor, 
dosing with ritonavir increased the exposure of nirmatrelvir. Highest observed mean Cmax and 
AUClast was 5.09 µg/mL and 64.26 µg•h/mL, respectively, at 750 mg nirmatrelvir dosed with 
ritonavir. The mean half-life of nirmatrelvir was approximately 2 hours when administered 
alone and increased to approximately 6-13 hours when coadministered with ritonavir. Dosing 
with a high-fat meal modestly increased the exposure of nirmatrelvir (approximately 15% 
increase in mean Cmax and 1.6% increase in mean AUClast).
PK data on Day 1, Day 5 and Day 10 following multiple oral administration of 
nirmatrelvir/ritonavir 75/100 mg, 250/100 mg, and 500/100 mg q12h suggest a less than dose 
proportional increase in exposure at steady state. Following multiple dosing over 10 days, 
steady state was achieved on Day 2 with approximately 2-fold accumulation. Day 5 and Day 
10 exposure was similar at all doses. The absorption of nirmatrelvir/ritonavir in fasted state 
occurred with the median Tmax ranging between 0.75 hours to 2.75 hours across all doses 
upon single or repeat dosing.
Nirmatrelvir plasma exposure for the tablet treatment was lower compared to the suspension, 
with approximately 19% and 44% lower geometric mean AUClast and Cmax values, 
respectively.
The primary route of elimination of nirmatrelvir when administered with ritonavir was renal 
excretion of intact drug. A total of 49.6% and 35.3% of the administered dose of nirmatrelvir
300 mg was recovered in urine and feces, respectively. Nirmatrelvir was the predominant 
drug-related entity with small amounts of metabolites arising from hydrolysis reactions in 
excreta. After normalization of the data to 100% mass balance, unmetabolized nirmatrelvir
represented 82.5% of the drug-related material, with 55.0% in urine and 27.5% in feces. In 
plasma, the only drug-related entity quantifiable 19F-NMR was unchanged nirmatrelvir.
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2.3. Benefit/Risk Assessment
Neither nirmatrelvir/ritonavir nor rosuvastatin are expected to provide any clinical benefit to 
healthy participants in this study. This study is designed primarily to further the 
understanding of human PK, metabolism, and elimination of nirmatrelvir/ritonavir.
Based on data from Study C4671001, the clinical safety profile of nirmatrelvir/ritonavir 
appears to be acceptable at single doses up to 1500 mg alone and up to 2250 mg administered 
with ritonavir (100 mg at -12h, 0h, 12h), split dosing administration (3 doses of 750 mg) at 
short intervals (approximately 2 hours from the previous dose), and at repeated daily doses 
administered orally for 10 days of up to 500 mg nirmatrelvir q12h with 100 mg ritonavir 
q12h. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of nirmatrelvir/ritonavir may be found in the IB, which is the SRSD for this 
study. Refer to the Study Intervention(s) table in Section 6.1 for a complete description of 
SRSDs, including SRSDs for required NIMPs/AxMPs, for this study.
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2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention: Nirmatrelvir
Dysgeusia
When co-administered with ritonavir in Study C4671005, dysgeusia was 
recorded as an AE by 6% of participants receiving nirmatrelvir/ritonavir 
compared to <1% of participants receiving placebo
Participants may utilize 
recommendations to alleviate 
symptoms of dysgeusia while taking 
treatment such as peppermint 
post-dose. Dosing recommendations 
will be provided to the participant.
Emesis
Sporadic emesis was observed at ≥100 mg/kg/day of nirmatrelvir in the 15-
day NHP toxicology study. 
AEs will be monitored and 
participants may receive antiemetics.
Hypertension
Transient increases in systolic, diastolic and mean BP were observed in pre-
clinical studies. When co-administered with ritonavir in Study C4671005 
(adults at high risk for severe disease) a small imbalance in hypertension 
AEs (1% vs < 1%) was reported.
Vital signs and all AEs will be 
monitored in the study.
Study Intervention: Ritonavir
Gastrointestinal disturbances 
(including diarrhea, nausea, vomiting, 
and abdominal pain)
Frequently reported adverse reaction in patients who are HIV-positive at 
600 mg BID.
Lower dose of 100 mg q12h is used 
in this study. There is a short 
duration of treatment (three periods 
with a single dose each). There will 
be close observation of AEs.
Neurological disturbances 
(eg, paresthesia, including oral 
paresthesia, dysgeusia, and dizziness)
Frequently reported adverse reaction in patients who are HIV-positive at 
600 mg BID.
Lower dose of 100 mg used in this 
study. There will be close 
observation of AEs.
Rash (most commonly reported as 
erythematous and maculopapular, 
followed by pruritic)
Frequently reported adverse reaction in patients who are HIV-positive at 
600 mg BID.
Lower dose of 100 mg used in this 
study. There will be close 
observation of AEs and monitoring 
through physical exams. A full 
physical exam will be conducted at 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
screening or Day -1, Period 1. Brief 
physical exams will be conducted at 
Day 5, Period 1; Day 2, Period 2; 
and Day 5, Period 2, with additional 
exam(s) at the discretion of the 
investigator. Brief physical exams 
include skin assessment, and may be 
updated based on AEs if appropriate.
If needed therapeutic interventions 
per standard of care may be 
provided.
Fatigue/Asthenia
Frequently reported adverse reaction in patients who are HIV-positive at 
600 mg BID.
Lower dose of 100 mg used in this 
study. There will be close 
observation of AEs. Fatigue (low 
energy or tiredness) will be assessed 
through collection of daily signs and 
symptoms and will also be assessed 
through targeted physical 
examinations when performed 
during the study visits.
Haematological abnormalities
Adverse reactions in clinical studies and post-marketing in adult patients 
include decreased white blood cells, decreased haemoglobin, decreased 
neutrophils, increased eosinophils, and thrombocytopenia (common), as 
well as increased neutrophils (uncommon).
Lower dose of 100 mg used in this 
study. There will be close 
observation of AEs and monitoring 
through lab testing. Safety lab tests 
will be conducted at screening and 
on Day -1, Period 1; Day 3, 
Period 1; Day 5, Period 1; Day 3, 
Period 2; and Day 5, Period 2, with 
additional test(s) at the discretion of 
the investigator.
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention: Rosuvastatin
Skeletal muscle effects (eg, myopathy 
and rhabdomyolysis)
Cases of myopathy and rhabdomyolysis with acute renal failure secondary 
to myoglobinuria have been reported. These risks can occur at any dose 
level, but are increased at the highest dose (40 mg).
Only single dosing of 10 mg will be 
used in this study (one single dose 
per period). There will be close 
observation of AEs and monitoring 
through targeted physical exams and 
lab testing, including monitoring of 
creatinine kinase levels. A full
physical exam will be conducted at 
screening or Day -1, Period 1. Brief 
physical exams will be conducted at 
Day 5, Period 1; Day 2, Period 2; 
and Day 5, Period 2, with additional 
exam(s) at the discretion of the 
investigator. Brief physical exams 
include skeletal muscle assessment, 
and may be updated based on AEs if 
appropriate. Safety lab tests will be 
conducted at screening and on 
Day -1, Period 1; Day 3, Period 1; 
Day 5, Period 1; Day 3, Period 2; 
and Day 5, Period 2, with additional 
test(s) at the discretion of the 
investigator.
Liver enzyme abnormalities
Increases in serum transaminases have been reported. In most cases, 
elevations were transient and resolved or improved on continued therapy or 
after a brief interruption in therapy. There were two cases of jaundice, for 
which a relationship to rosuvastatin therapy could not be determined, which 
resolved after discontinuation of therapy. There were no cases of liver 
failure or irreversible liver disease in these trials.
Only single dosing of 10 mg will be 
used in this study (one single dose 
per period). Liver enzyme tests will 
be performed before dosing, after 
dosing, and prior to discharge, or at 
any point if signs or symptoms of 
liver injury occur. Safety lab tests 
will be conducted at screening and 
on Day -1, Period 1; Day 3, 
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Potential Risk of Clinical 
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Summary of Data/Rationale for Risk
Mitigation Strategy
Period 1; Day 5, Period 1; Day 3, 
Period 2; and Day 5, Period 2, with 
additional test(s) at the discretion of 
the investigator.
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions including Stevens-Johnson syndrome 
and drug reaction with eosinophilia and systemic symptoms, which could be 
life-threatening or fatal, have been reported with rosuvastatin.
Only single dosing of 10 mg will be 
used in this study (one single dose 
per period). There will be close 
observation of AEs and monitoring 
through targeted physical exams. A 
full physical exam will be conducted 
at screening or Day -1, Period 1. 
Brief physical exams will be 
conducted at Day 5, Period 1; Day 2, 
Period 2; and Day 5, Period 2, with 
additional exam(s) at the discretion 
of the investigator. Brief physical 
exams include skin assessment, and 
may be updated based on AEs if 
appropriate.
Study Procedures
Venipuncture will be performed 
during the study.
There is the risk of bleeding, bruising, hematoma formation, and infection at 
the venipuncture site.
Only appropriately qualified 
personnel will obtain the blood 
draw.
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2.3.2. Benefit Assessment
Neither nirmatrelvir/ritonavir nor rosuvastatin are expected to provide any clinical benefit to 
healthy participants. This study is designed primarily to generate safety, tolerability, and PK 
data for further clinical development. Rosuvastatin is contraindicated according to the SmPC3
in patients with hypersensitivity to rosuvastatin or to any of the excipients, in patients with 
active liver disease including unexplained, persistent elevations of serum transaminases and 
any serum transaminase elevation exceeding 3 times the ULN, in patients with severe renal 
impairment (creatinine clearance <30 mL/min), in patients with myopathy, in patients 
receiving concomitant ciclosporin, and during pregnancy and lactation and in WOCBP not 
using appropriate contraceptive measures. All such patients are excluded from participating 
in this study as listed in Section 5.2.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with nirmatrelvir/ritonavir and rosuvastatin are justified by the 
anticipated benefits that may be afforded to participants with mild-to-moderate COVID-19.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary:
Primary:
To assess the effect of multiple doses of 
nirmatrelvir/ritonavir on the plasma 
pharmacokinetics of a single, oral dose of 
rosuvastatin in healthy participants.
AUCinf, Cmax, of rosuvastatin.
Secondary:
Secondary:
To further characterize the plasma 
pharmacokinetics of a single, oral dose of 
rosuvastatin administered with 
nirmatrelvir/ritonavir.
To evaluate the safety and tolerability of a 
single oral dose of rosuvastatin when 
co-administered with nirmatrelvir/ritonavir.
AUClast, Tmax, t½, CL/F, and Vz/F of 
rosuvastatin.
Vital signs, laboratory tests and 
adverse events.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, randomized, fixed sequence, multiple-dose, open-label study of the effect 
of nirmatrelvir/ritonavir on rosuvastatin PK in healthy adult participants.
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A total of approximately 12 healthy male and/or female participants will be enrolled in the 
study. Participants who discontinue from the study may be replaced at the sponsor’s 
discretion.
Participants will be screened within 28 days prior to the first dose of investigational product.
Participants will report to the CRU the day prior to Day 1 dosing (ie, Day -1) in Period 1. 
Participants will remain in the CRU for a total of 11 days and 10 nights (including Period 1 
and Period 2). To adequately remove any drug effects of rosuvastatin from Period 1 to 
Period 2, there will be a minimum 5-day washout period between the 2 rosuvastatin dosing 
events. The total rosuvastatin PK will then be assessed over 72 hours.
Participants will receive 2 treatments across 2 periods, as outlined in Table 3 below:
Table 3.
Treatment Sequence
Sequence
Period 1
Washout
Period 2
Sequence 1 (N = 12)
Treatment A
At least 5 days between 
the 2 rosuvastatin dosing 
events
Treatment B
N = number of enrolled participants.

Treatment A (rosuvastatin, Reference): Single oral administration of rosuvastatin 10 mg
tablet on Day 1 in the morning (AM dose).

Treatment B (rosuvastatin + nirmatrelvir/ritonavir, Test): Nirmatrelvir/ritonavir 300 mg 
(2 × 150 mg)/100 mg tablets q12h (BID) for 2 days (Day 1 morning [AM] and evening 
[PM] and Day 2 morning [AM], 3 doses total) with a single oral administration of 
rosuvastatin 10 mg tablet on Day 2 in the morning (AM dose). Nirmatrelvir and ritonavir 
will be dosed within no more than 5 minutes of each other. Rosuvastatin single dose will 
be dosed within 5 minutes after the Day 2 morning (AM) nirmatrelvir/ritonavir dose.
The expected duration of participation from Screening to the follow-up telephone contact 
will be approximately 11 weeks.
If a participant has any clinically significant, study related abnormalities at the conclusion of 
a scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the participant may be asked to remain in the CRU 
until such abnormalities are deemed not clinically significant, or it is safe for outpatient 
follow-up.
A safety follow-up call will be made to participants approximately 28 to 35 days from 
administration of the final dose of study intervention.
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4.2. Scientific Rationale for Study Design
An in vitro DDI risk analysis for nirmatrelvir in accordance with the EMA 2012 DDI 
guidance was conducted using data reported in the Population Modeling Analysis Report 
(PMAR-13234). Nirmatrelvir showed potential for OATP1B1 inhibition (Table 4).
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Table 4.
Assessment of Risk for in Vivo DDIs Between Nirmatrelvir and Co-administered Substrates of OATP1B1 
Transporter, Based on the 2012 EMA Drug Interactions Guideline
Transporter
IC50 (µM)
Kia (µM)
Cmax,u
(µM)
50 × Cmax,u
(µM)
Iin,max,ub
(µM)
25 × Iin,max,u
Criteria for 
Potential DDI
Rh(≥0.04)
Rr(≥0.02)
DDI Risk
(Yes/No)
OATP1B1
44.4
44.4
NA
NA
3.88
97
Ki ≤ (25×Iin,max,u)
0.087
NA
Yes
BCRP
>1000
>1000
NA
NA
NA
NA
Ki ≤ (0.1 × 
Dose/250 mL)
NA
NA
No
OAT3
520.6
520.6
1.96
98
NA
NA
Ki ≤ (50 × Cmax,u)
NA
0.004
No
Cmax,u = Maximum unbound inhibitor concentration (clinical oral dose of 300 mg nirmatrelvir + 100 mg ritonavir BID - mean steady state.
total Cmax × fu,p = 1.96 μM, from PMAR-13234.
fu,p = Fraction unbound in human plasma = 0.31; IC50 = 50% inhibitory concentration.
Iin,max,u = Maximal unbound inhibitor concentration in the hepatic inlet; NA= not applicable; Ki = concentration at half-maximal rate of inhibition; 
RB = Blood-to-plasma ratio (0.6); Rh = Iin,max,u/Ki; Rr = Cmax,u/Ki.
a.
The estimated Ki values were assumed to be equal to the IC50 values for all transporter inhibition assays, based on the respective probe substrate 
concentration-to-Km ratio.
b.
Iin,max,u = fu,b × Iin,max,b = fu,b × [Cmax,b + (Fa Fg × ka × Dose)/Qh] = fu,p /RB × [Cmax × RB + (Fa Fg × ka × Dose)/Qh].
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Nirmatrelvir shows an Rh of 0.087, which is above the EMA cutoff criteria of 0.04. Therfore, 
a clinical interaction study with an OATP1B1 substrate is needed to assess the effect of 
nirmatrelvir/ritonavir on this transporter. Rosuvastatin is used in DDI studies as a substrate to 
assess changes in activity of OATP1B1.5
Several in vitro studies suggest that ritonavir is also an inhibitor of OATP1B1, with reported 
IC50 values ranging from 0.497 to 6.1 µM.6,7,8 Clinical studies evaluating the impact of 
ritonavir on substrates of OATP1B1 are few and confounded by 1) simultaneous 
administration with another protease inhibitor that is also an OATP inhibitor, and 2) 
coadministration with an OATP substrate that is also a CYP3A4 substrate. In one clinical 
study of 200 mg ritonavir co-administered with mebrofenin, a substrate of OATPs for uptake 
and MRP2 for efflux, mebrofenin AUC increased 1.3× with a 22% corresponding decrease in 
biliary excretion.9
Rosuvastatin is also a subtrate for BCRP and OAT3 transport in addition to OATP1B1. 
Nirmatrelvir did not show potential for BCRP or OAT3 inhibition using the EMA guidance 
Table 5). In vitro studies suggest that ritonavir might inhibit BCRP (IC50 = 19.5-33.9 µM), 
but not OAT3.6,10,11,12 Therefore, inhibitory effects by nirmatrelvir on BCRP and OAT3 are 
not anticipated to confound the assessment of nirmatrelvir’s impact on rosuvastatin PK. In 
order to mitigate the risk of BCRP inhibition by ritonavir, CP-1 (an endogenous biomarker of 
OATP1B1 inhibition, see Section 8.7) will be collected to deconvolute the mechanism of 
rosuvastatin DDI by nirmatrelvir/ritonavir.
Rosuvastatin has a t½ of ~20 hours, hence the requirement of 5-day washout between the 
2 rosuvastatin dosing events.13 Plasma PK samples of rosuvastatin will be collected over 
3 days post dosing to ensure that the majority of rosuvastatin is recovered.
Nirmatrelvir/ritonavir has been shown to reach steady-state exposure by Day 2 following 
q12h dosing of 300 mg/100 mg. Thus, nirmatrelvir/ritonavir will be dosed over 2 days 
(3 doses) in the Treatment arm to ensure steady-state is reached prior to administering 
rosuvastatin.
Additional information for nirmatrelvir/ritonavir may be found in the IB. The information for 
rosuvastatin may be found in the approved Belgian SmPC (Crestor®).
4.2.1. Choice of Contraception/Barrier Requirements
Human reproductive safety data are limited for nirmatrelvir/ritonavir, but there is no 
suspicion of human teratogenicity based on the intended pharmacology of the compound. 
Therefore, the use of a highly effective method of contraception is required (see Appendix 4).
4.3. Justification for Dose
This study is designed to estimate the effect of steady-state nirmatrelvir/ritonavir 
300 mg/100 mg q12h dosing on the pharmacokinetics of a 10 mg single dose of rosuvastatin.
The dose of nirmatrelvir/ritonavir 300/100 mg BID for 5 days is the approved therapeutic 
dose and treatment duration under emergency use authorization. This dose is lower than the 
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highest dose evaluated in the Phase 1 C4671001 study and is safe and well-tolerated.
Nirmatrelvir/ritonavir reaches steady-state by Day 2 of dosing.
Rosuvastatin is a synthetic statin that has been developed for the treatment of patients with 
dyslipidemia. Rosuvastatin is administered orally and approximately 50% of the drug is 
absorbed resulting in 20% absolute bioavailability.14 The Cmax is reached 3 to 5 hours after 
administration of a 10 mg to 80 mg oral dose. Both the Cmax and AUC increase in proportion 
to the dose from 10 mg to 80 mg dose range.15 Rosuvastatin mostly goes through biliary and 
renal excretion with minimal metabolism. The t½ is ~20 hours.13 After 20 mg oral dose, 
90% of the dose is recovered from feces and 10% is recovered from the urine, mostly as 
unchanged drug.13 Active secretion accounts for more than 90% of renal clearance.14
In a single dose escalation study, rosuvastatin was safe and well tolerated at doses up to 
80 mg.15 The most common AEs reported were headache and rash. There was no evidence of 
a relationship between the frequency of AEs and rosuvastatin dose. No SAEs were 
reported.14 Most DDI studies involving rosuvastatin as a substrate are conducted at 10 mg or 
20 mg dose level.16,17,18
In previous drug interaction studies of protease inhibitors boosted with 100 mg ritonavir 
co-administered with 10 mg rosuvastatin, rosuvastatin AUC increased 1.48 – 3.13-fold 
relative to rosuvastatin dosed alone.19,20 Given this level of previously observed AUC 
increase, a 10mg dose would be comparable to a ~20-30 mg dose, which is still below the 
maximum observed tolerable dose of 80 mg.21 This level of increased systemic exposure is 
still considered safe and well tolerated in both Western and Asian populations. In these 
previous protease inhibitor/rosuvastatin DDI studies, study drugs were well-tolerated, with 
no SAEs attributed to rosuvastatin dosing.19,20
Rosuvastatin is not expected to significantly affect the exposures of nirmatrelvir/ritonavir. 
Thus, the combination of 300 mg/100 mg nirmatrelvir/ritonavir and 10 mg rosuvastatin is 
expected to be tolerated by healthy participants.
4.4. End of Study Definition
The end of the study is defined as the date of the last scheduled procedure shown in the SoA
for the last participant in the trial.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last scheduled procedure shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
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appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and female participants aged 18 years (or the minimum age of consent in 
accordance with local regulations) or older at screening who are overtly healthy as 
determined by medical evaluation including medical history, physical examination, 
laboratory tests, vital signs and standard 12-lead ECG.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Other Inclusion Criteria:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Female participants must have a negative pregnancy test.
4. BMI of 16-32 kg/m2; and a total body weight >50 kg (110 lb).
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Positive test result for SARS-CoV-2 infection on Day -1.
2. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy).
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
History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, or HCVAb. Hepatitis B vaccination is allowed.
3. Clinically relevant abnormalities requiring treatment (eg, acute myocardial infarction, 
unstable ischemic conditions, evidence of ventricular dysfunction, serious tachy or 
bradyarrhythmias) or indicating serious underlying heart disease (eg, prolonged PR 
interval, cardiomyopathy, heart failure greater than NYHA 1, underlying structural 
heart disease, Wolff Parkinson-White syndrome).
4. Any medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality or other conditions that may 
increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.
5. Participants, who according to the product label for rosuvastatin, would be at 
increased risk if dosed with rosuvastatin, including participants with myopathy and 
with hypersensitivity to rosuvastatin or any of its excipients.
Prior/Concomitant Therapy:
6. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details).
7. Current use of any prohibited concomitant medication(s) or participant unwilling or 
unable to use a required concomitant medication(s). Refer to Section 6.9 Prior and 
Concomitant Therapy.
8. Participant who have received a COVID-19 vaccine within 7 days before screening or 
admission, or who are to be vaccinated with a COVID-19 vaccine at any time during 
the study confinement period.
Prior/Concurrent Clinical Study Experience:
9. Previous administration with an investigational product (drug or vaccine) within 
30 days (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). Participation in 
other studies involving study intervention within 30 days prior to study entry. A 
participant may be eligible even if they are in the follow-up phase of an 
investigational study as long as they have not received treatment in that study for at 
least 1 month.
Diagnostic Assessments:
10. A positive urine drug test. A single repeat for positive drug screen may be allowed.
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11. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic) for 
participants <60 years; and ≥150/90 mm/Hg for participants ≥60 years old, following 
at least 5 minutes of supine rest. If systolic BP is ≥ 140 or 150 mm Hg (based on age) 
or diastolic ≥90 mm Hg, the BP should be repeated 2 more times and the average of 
the 3 BP values should be used to determine the participant’s eligibility.
12. Renal impairment as defined by an eGFR in adults of <60 mL/min/1.73m2. Based 
upon participant age at screening, eGFR is calculated using the CKD-EPI formula in 
Section 10.6.2 to determine eligibility and to provide a baseline to quantify any 
subsequent kidney safety events.
For eligibility assessment based upon estimated renal function, the higher of the 
screening and baseline eGFR values may be used.
13. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 
complete LBBB, signs of an acute or indeterminate age myocardial infarction, STT 
interval changes suggestive of myocardial ischemia, second or third degree AV block, 
or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 ms, or QRS 
exceeds 120 ms, the ECG should be repeated twice and the average of the 3 QTcF or 
QRS values used to determine the participant’s eligibility. Computer interpreted
ECGs should be overread by a physician experienced in reading ECGs before 
excluding a participant.
14. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the studyspecific laboratory and confirmed by a single 
repeat test, if deemed necessary:

ALT, AST, Bili >1.0 × ULN.
Other Exclusion Criteria:
15. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
16. Use of tobacco or nicotine containing products in excess of the equivalents of 
5 cigarettes per day or 2 chews of tobacco per day.
17. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
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18. History of sensitivity reactions to ritonavir or rosuvastatin, or any of the formulation 
components of nirmatrelvir, ritonavir, or rosuvastatin.
19. Pregnant or breastfeeding women.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4,
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. The investigator or designee will advise the participant to seek advice about the 
donation and cryopreservation of germ cells prior to the start of study intervention, if 
applicable.
At time points indicated in SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit.
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample.

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks 
(except grapefruit or grapefruit related- citrus fruit juices—see below) may be 
consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after morning (AM) dosing.

Dinner will be provided approximately 9 to 10 hours after morning (AM) dosing.

An evening snack may be permitted.
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
Participants will refrain from consuming red wine, grapefruit, or grapefruit -related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.3. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine- containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.4. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP and pulse rate 
measurements), eating, and drinking beverages other than water during the first 
4 hours after the morning (AM) dose on PK sampling days.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct.
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For the purposes of this protocol, study intervention refers to nirmatrelvir 150 mg tablet, 
ritonavir 100 mg tablet and rosuvastatin 10 mg tablet.
6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
PF-07321332 
(nirmatrelvir) tablets
Ritonavir tablets
Rosuvastatin tablets
Type
Drug
Drug
Drug
Use
Test
Test
Reference, Test
IMP or NIMP/AxMP
IMP
NIMP/AxMP
NIMP/AxMP
Dose Formulation
Tablet
Tablet
Tablet
Unit Dose Strength(s)
150 mg
100 mg
10 mg
Dosage Level(s)
300 mg q12h for 2 days 
(Day 1 morning [AM] 
and evening [PM] and 
Day 2 morning [AM], 3 
doses total)
100 mg q12h for 2 days 
(Day 1 morning [AM] 
and evening [PM] and 
Day 2 morning [AM], 3 
doses total)
10 mg single dose (for 
both Treatment A and 
Treatment B)
Route of 
Administration
Oral
Oral
Oral
Sourcing
Provided centrally by 
the sponsor.
Provided locally by the 
CRU.
Provided locally by the 
CRU.
Packaging and 
Labeling
Study intervention will 
be provided in a bulk 
container (HDPE). Each 
bottle will be labeled as 
required per country 
requirement.
Study intervention will 
be provided in the
commercial presentation 
as sourced by site. Each 
container will be labeled 
as required per country 
requirement.
Study intervention will 
be provided in the 
commercial 
presentation as sourced 
by site. Each container 
will be labeled as 
required per country 
requirement.
SRSD
IB
IB
SmPC
Current/Former 
Name(s) or Alias(es)
Nirmatrelvir 
(PF-07321332)
As available locally
As available locally
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Study Arm/Period(s)
Arm/Period Title
Treatment A (rosuvastatin, 
Reference)
Treatment B (rosuvastatin + 
nirmatrelvir/ritonavir, Test)
Arm/Period
Description
Single oral dose of 
rosuvastatin 10 mg tablet on 
Day 1 in the morning (AM 
dose).
Nirmatrelvir/ritonavir 300 mg (2 × 150 mg)/ 
100 mg tablets q12h (BID) for 2 days (Day 1 
morning [AM] and evening [PM] and Day 2 
morning [AM], total of 3 doses) with a single 
oral dose of rosuvastatin 10 mg tablet on Day 2 
in the morning (AM dose). Nirmatrelvir and 
ritonavir will be dosed within no more than 5 
minutes of each other. Rosuvastatin single dose 
will be dosed within 5 minutes after the Day 2 
morning (AM) nirmatrelvir/ritonavir dose.
Nirmatrelvir 150 mg tablets will be supplied to the CRU in bulk along with individual dosing 
containers for unit dosing.
Ritonavir (Norvir® or other local commercialized product) 100 mg tablets will be supplied 
locally by the CRU.
Rosuvastatin (Crestor® or other local commercialized product) 10 mg tablets will be supplied 
locally by the CRU. 
6.1.1. Administration
For Treatment A, following an overnight fast of at least 10 hours, participants will receive on 
Day 1 in the morning (AM dose) a single 10 mg (1 × 10 mg tablet) dose of rosuvastatin at 
approximately 0800 hours (plus or minus 2 hours).
For Treatment B, participants will receive 300 mg (2 × 150 mg tablet) nirmatrelvir 
administered orally with 100 mg (1 × 100 mg tablet) ritonavir q12h for 2 days (Day 1 
morning [AM] and evening [PM] and Day 2 morning [AM], 3 doses total) starting at 
approximately 0800 hours (plus or minus 2 hours). On Day 1, the nirmatrelvir/ritonavir doses 
will be administered after at least a 2 hour fast. On Day 2, following an overnight fast of at 
least 10 hours, the final (third) nirmatrelvir/ritonavir dose will be co-administered with a 
single 10 mg (1 × 10 mg tablet) dose of rosuvastatin in the morning (AM dose). Nirmatrelvir 
and ritonavir will be dosed within no more than 5 minutes of each other. Rosuvastatin single 
dose will be dosed within 5 minutes after the Day 2 morning (AM) nirmatrelvir/ritonavir 
dose.
Investigator site personnel will administer study intervention during each period with 
ambient temperature water to a total volume of approximately 240 mL.  For Treatment B,
when nirmatrelvir/ritonavir is co-administered with rosuvastatin for the Day 2 morning (AM) 
dose, participants may receive additional ambient temperature water up to 100 mL, if needed. 
This will be documented by the site. Participants will swallow the study intervention whole, 
and will not manipulate or chew the study intervention prior to swallowing.
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Administration of study intervention(s) will be performed by an appropriately qualified and 
trained member of the study staff as allowed by local, state, and institutional guidance.
Following administration of study intervention(s), participants will be observed for the time 
of residence within the CRU by an appropriately qualified and trained member of the study 
staff. Appropriate medication and other supportive measures for management of a medical 
emergency will be available in accordance with local guidelines and institutional guidelines.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the CRU local/site 
procedures.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record.
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8. Further guidance and information for the final disposition of unused study 
interventions are provided in the CRU’s local/site procedures. All destruction must be 
adequately documented. If destruction is authorized to take place at the investigator 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider or
participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.
Tablets will be prepared at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist). 
The tablets will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements.
6.3. Assignment to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Blinding
This is an open-label study.
6.4.1. Blinding of Participants
Participants will be unblinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention.
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6.4.3. Blinding of the Sponsor
Sponsor staff will be unblinded to participants’ assigned study intervention.
As this is an open-label study, the sponsor may conduct unblinded reviews of the data during 
the course of the study for the purpose of safety assessment, facilitating PK/PD modeling, 
and/or supporting clinical development.
6.5. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
No dose modification is anticipated.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician. 
6.8. Treatment of Overdose
For this study, any dose of nirmatrelvir greater than 600 mg, ritonavir greater than 200 mg, or 
rosuvastatin greater than 20 mg within a 24-hour time period [±2 hours] will be considered 
an overdose.
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
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5. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case by case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
As nirmatrelvir and ritonavir are both primarily metabolized by CYP3A4, concomitant use of 
any medications or substances that are strong inducers of CYP3A4 are prohibited within 
14 days plus 5 half-lives prior to dosing of study intervention. Additionally, ritonavir and 
nirmatrelvir are inhibitors of CYP3A4. Therefore, medications highly dependent on CYP3A4 
for clearance and for which elevated plasma concentrations may be associated with serious 
and/or life-threatening events are not permitted during dosing of nirmatrelvir/ritonavir,
through 4 days after the last dose of nirmatrelvir/ritonavir.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following:

AE requiring discontinuation in investigator’s view,

Pregnancy,
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
Positive COVID-19 test.
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
7.1.1. Potential Cases of Acute Kidney Injury
Participants exposed to IMP demonstrating transient or sustained increase in Screat (with 
decrease in Screat-based eGFR or eCrCL) require expedited evaluation to differentiate AKI 
from DICI. DICI is defined as transporter-mediated effect related to altered renal tubular 
creatinine handling without histological injury.
Differentiating Acute Kidney Injury from DICI:
AKI may be due to one or more types of injury, including DIKI. Differentiation of DIKI 
from other causes of AKI and from DICI may require clinical, radiographic, histopathologic, 
and laboratory assessments, as well as nephrology consultation.
Both AKI (including DIKI) and DICI are associated with (i) confirmed Screat increase 
≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours OR (ii) confirmed Screat increase ≥1.5 times 
baseline (known or suspected to have occurred within the prior 7 days).
Only AKI (including DIKI) is associated with

For ADULT and PEDIATRIC participants, (i) simultaneous, confirmed serum cystatin C 
(Scys) increase and confirmed Screat increase OR (ii) confirmed albuminuria increase 
(see Appendix 6 for Grades A1 to A3 quantitation) OR (iii) urine volume <0.5 mL/kg/h 
for 6 consecutive hours.

For ADULTS only, AKI is associated with decrease in Screat-based eGFR and combined 
Screat-Scys-based eGFR (when available).
Regardless of the presence or absence of increase in Screat, DIKI and other causes of AKI 
may be suspected if either there is (i) new-onset or worsening albuminuria or proteinuria are 
detected or (ii) urine volume (if measured) is <0.5 mL/kg/h for 6 consecutive hours.
Only DICI is associated with:

For ADULT participants only, confirmed Screat increase without confirmed increase in 
reflex Scys AND confirmed Screat-based eGFR decrease without confirmed combined 
Screat-Scys-based eGFR decrease.
The participant should return to the site for evaluation as soon as possible, preferably within 
48 hours of awareness of the abnormal results. Evaluation should include physical 
examination, laboratory tests, detailed medical and surgical history, review of all medications 
(including recreational drugs and supplements [herbal]), family history, sexual history, travel 
history, blood transfusion, and potential occupational exposure to chemicals. If appropriate, 
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nephrology consultation may be recommended to facilitate differentiation of renal 
parenchymal disease, pre-renal azotemia, and post-renal obstruction. All confirmed cases of 
clinically relevant decrease in kidney function should be considered potential cases of DIKI 
if no other reason for the kidney function abnormalities has been found.
7.1.2. ECG Changes
A participant who meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 

QTcF >500 ms.

Change from baseline: QTcF >60 ms and QTcF >450 ms.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.3. Stopping Rules
Dosing will be halted at any time if 1 of the following circumstances occurs and it is 
determined by the investigator that the occurrence is at least possibly related to the 
administration of study intervention:

A SAE (eg, a serious AE considered at least possibly related to study intervention
administration) in 1 participant.

Severe NSAE (eg, severe NSAEs considered at least possibly related to study 
intervention administration) in 2 participants, independent of whether it is within or 
not within the same SOC.
When stopping rules are met, a data review will be conducted by the sponsor and 
investigator. If integrated analysis of available data leads to the conclusion that further dosing 
is justified, an amendment to the protocol may be required if additional safety monitoring is 
warranted. 
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Refused further study procedures;

Lost to follow-up;

Death;
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
Study terminated by sponsor;

Investigator’s decision;

Pregnancy.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
7.3. Lost to Follow-Up
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
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The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative and Baseline Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
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addition, other clinical assessments or specimen collections may not need to be repeated, as 
appropriate.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
255 mL (for both Periods 1 and 2). The actual collection times of blood sampling may 
change. Additional blood samples may be taken for safety assessments at times specified by 
Pfizer, provided the total volume taken during the study does not exceed 550 mL during any 
period of 56 consecutive days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
Medical history collected will include a history of prior illegal drug, alcohol, and tobacco 
use, as well as blood donation with prior 60 days. Demographics collected will include 
participant’s race, ethnicity, age, and gender.
8.2. Efficacy Assessments
Efficacy parameters are not evaluated in this study.
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems.
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A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, skin and skeletal muscle, and participant-reported
symptoms.
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source record 
and will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
BP and pulse rate assessments will be performed after collection of ECGs and prior to 
collection of blood draws if scheduled at the same time.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.2.2. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
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8.3.3. Electrocardiograms
Standard 12-lead ECGs will be collected at times specified in the SoA section of this
protocol using an ECG system that automatically calculates the HR and measures PR, QT, 
QTcF, and QRS intervals. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 5 minutes in a supine position and prior to any blood draws or vital 
sign measurements.
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected will be recorded.
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the mean 
value from the triplicate measurements for any post dose QTcF interval is increased by 
≥60 ms from the baseline and is >450 ms; or b) an absolute QT value is ≥500 ms for any 
scheduled ECG. If either of these conditions occurs, then a single ECG measurement must be 
repeated at least hourly until QTcF values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If a) a post dose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.3.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
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All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 48 hours after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 6 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
Participants may undergo random urine drug testing at the discretion of the investigator.
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments
Participants will be tested for COVID-19 infection per local procedures. Additional testing 
may be required by local regulations or by the PI.
8.3.6. Pregnancy Testing
A urine or serum pregnancy test is required at screening. Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. 
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will be required at the baseline visit prior to 
starting the study intervention. Pregnancy tests will also be done whenever 1 menstrual cycle 
is missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study. Pregnancy tests may also be repeated if requested by 
IRBs/ECs or if required by local regulations. If a urine test cannot be confirmed as negative 
(eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded if the serum pregnancy result is positive.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
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and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form/PSSA.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form/PSSA immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
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8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form or via PSSA regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form or via PSSA. Since the exposure information does not pertain to the participant 
enrolled in the study, the information is not recorded on a CRF; however, a copy of 
the completed report is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial report. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
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8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion, inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form or via PSSA. When EDB occurs in the setting of 
environmental exposure, the exposure information does not pertain to the participant enrolled 
in the study, so the information is not recorded on a CRF. However, a copy of the completed 
report is maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form or via PSSA
regardless of whether there is an associated SAE. Since the information about the 
occupational exposure does not pertain to a participant enrolled in the study, the information 
is not recorded on a CRF; however, a copy of the completed report is maintained in the 
investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
Not applicable.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
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8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form/PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, such medication errors occurring to a study participant are recorded on the 
medication error page of the CRF, which is a specific version of the AE page and, if 
applicable, any associated serious and nonserious AE(s), are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form/PSSA only when associated with an SAE.
8.5. Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of rosuvastatin, 
nirmatrelvir, and ritonavir as specified in the SoA. Instructions for the collection and 
handling of biological samples will be provided in the laboratory manual or by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
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not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples will be used to evaluate the PK of rosuvastatin and confirm achievement of target 
steady-state trough concentration of nirmatrelvir and ritonavir. Samples collected for 
analyses of rosuvastatin and nirmatrelvir/ritonavir concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes.
Genetic analyses will not be performed on these PK plasma samples unless consent for this 
was included in the informed consent. Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of rosuvastatin and 
nirmatrelvir/ritonavir will be analyzed using a validated analytical method in compliance 
with applicable SOPs. Potential metabolites may be analyzed with either validated or 
exploratory methods.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol deviation. The IRB/EC will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
Retained research samples for genetics are not collected in this study.
8.7. Biomarkers
Collection of samples for biomarker research is also part of this study.
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The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA:

CP-1 biomarker plasma samples.
Blood samples will be collected for measurement of plasma concentrations of CP-1 as 
specified in the SoA. CP-1 will be collected during both Treatment A (Reference) and
Treatment B (Test) arms. Samples collected for measurement of plasma concentrations of 
CP-1 will be kept in amber vials covered with tin foil, stored at -80°C, and analyzed using a 
validated analytical method. Instructions for the collection and handling of biological 
samples will be provided in the laboratory manual or by the sponsor. The actual date and 
time (24-hour clock time) of each sample will be recorded. The actual times may change, but 
the number of samples will remain the same. All efforts will be made to obtain the samples at 
the exact nominal time relative to dosing.
CP-1 samples will be collected for exploratory research of CP-1 as an endogenous biomarker 
for OATP1B1 inhibition. CP-1 is a porphyrin metabolite from heme synthesis and relatively 
selective substrate for OATP1B1. Changes in CP-1 have been successfully applied as a 
biomarker for OATP1B1 modulation in vivo.22,23 For a statin that is not a substrate for 
CYP3A, such as pitavastatin and rosuvastatin, there is an approximately 1:1 relationship 
between changes in CP-1 and changes in statin AUC ratios upon treatment with OATP 
inhibitors (Table 5).
Table 5.
Changes in CP-1 and Statin AUC ratios
Precipitant Drug / Dose
CP-1 
AUCR
Pitavastain 
AUCR
Rosuvastatin 
AUCR
Reference
Rifampicin 600 mg
4.0
ND
5.0
Lai et al, 201624
Rifampicin 600 mg
3.5
2.8
2.4
Takehara et al, 201825
Rifampicin 600 mg
3.7
4.0
2.5
Mori et al, 202026
Rifampicin 300 mg
2.4
3.4
2.3
Mori et al, 202026
Rifampicin 300 mg
2.3
2.3
2.2
Takehara et al, 201825
Rifampicin 150 mg
1.5
2.5
1.6
Mori et al, 202026
Pimodivir 600 mg
1.4
1.5
ND
Kunze et al, 201827
Itraconazole 200 mg
0.9
0.77
1.4
Shen et al, 201828
Pitavastatin label29
Diltiazem 240 mg
1.0
1.1
ND
Shen et al, 201828; 
Pitavastatin label29
RO7049389 800 mg
3.0
1.9
ND
Feng et al, 202130
SLCO1B1*15/*15 vs WT
2.2
1.7
1.6
Mori et al, 201931
AUCR = AUC ratio = AUC in presence of Precipitant Drug/AUC in absence of Precipitant Drug.
8.7.1. Pharmacodynamic Biomarkers
Pharmacodynamic biomarkers are not collected in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
Not applicable. This is an estimation study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled/Randomly 
assigned to study 
intervention 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
screening.  
Safety Analysis Set
All participants who take at least 1 dose of study intervention. 
Participants will be analyzed according to the product they 
actually received.
PK Concentration Set
All participants who take at least 1 dose of study intervention 
and in whom at least 1 concentration value is reported.
PK Parameter Set
All participants who take at least 1 dose of study intervention 
and in whom at least 1 of the PK parameters of primary 
interest are reported.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. General Considerations
9.3.2. Primary Endpoint(s) Analysis
Natural log transformed AUCinf (if data permit), AUClast and Cmax will be analyzed using a 
mixed effect model with  treatment as a fixed effect and participant as a random effect. 
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Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model. The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CI for the ratios. Treatment A (rosuvastatin) will be the Reference 
treatment while Treatment B (rosuvastatin + nirmatrelvir/ritonavir) will be the Test 
treatment.
PK parameters, including plasma AUCinf, AUClast, Cmax, and Tmax, t½, CL/F and Vz/F of 
rosuvastatin will be summarized descriptively by treatment. For AUCinf, AUClast and Cmax, a 
listing of the individual participant ratios (Test/Reference) will be provided. Box and whisker 
plots for AUCinf, AUClast and Cmax, will be plotted by treatment.
The plasma concentrations of rosuvastatin will be listed and descriptively summarized by 
nominal PK sampling time and treatment. Individual participant, as well as mean and median 
profiles of the plasma concentration time data will be plotted by treatment using actual (for 
individual) and nominal (for mean and median) times respectively. Mean and median profiles 
will be presented on both linear and semi-log scales.
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
9.3.2.1. Definition of Endpoint(s)
Derivation of Pharmacokinetic Parameters
Plasma PK parameters of rosuvastatin will be derived (as data permit) from the 
concentration-time data using standard noncompartmental methods as outlined in the 
Table 6. Actual PK sampling times will be used in the derivation of rosuvastatin PK 
parameters when available. In the case that actual PK sampling times are not available, 
nominal PK sampling time will be used in the derivation of PK parameters.
Table 6.
Plasma Rosuvastatin PK Parameters Definitions
Parameter
Definition
Method of Determination
AUCinf*
Area under the concentration-time curve 
from time 0 extrapolated to infinity.
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point from the log-linear regression 
analysis.
AUClast**
Area under the plasma concentration-time 
profile from time 0 to the time of the last 
quantifiable concentration (Clast).
Linear/Log trapezoidal method.
Cmax
Maximum observed concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of 
first occurrence
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Table 6.
Plasma Rosuvastatin PK Parameters Definitions
Parameter
Definition
Method of Determination
t½*
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the loglinear 
concentration-time curve. Only those 
data points judged to describe the 
terminal loglinear decline will be used 
in the regression.
CL/F*
Apparent clearance
Dose/AUCinf
Vz/F*
Apparent volume of distribution
Dose/(AUCinf•kel)
*If data permit.
**Tlast will also be included in order to provide additional context for AUClast. Tlast will only be listed, not 
summarized.
9.3.3. Other Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported.
9.3.4. Other Analyses
9.3.4.1. Biomarker Assessment
CP-1 biomarker data will be listed and descriptively summarized by nominal sampling time 
and by treatment.
9.4. Interim Analyses
No interim analysis will be conducted for this study.
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9.5. Sample Size Determination
A sample size of 12 participants will provide adequate precision to estimate the relative 
bioavailability of rosuvastatin. The width of 90% CI for different estimated effects, with 
80% coverage probability, is presented in the Table 7.
Table 7.
Expected Width of 90% Confidence Interval for Different Possible 
Estimated Effects and Parameters of Interest
Parameter
Estimated Effect
(100*Test/Reference)
90% CI
CI Width
AUC
100%
84.94%
117.73%
32.78%
120%
101.93%
141.27%
39.34%
140%
118.92%
164.82%
45.90%
150%
127.41%
176.59%
49.18%
160%
135.91%
188.36%
52.45%
180%
152.90%
211.9%
59.01%
200%
169.89%
235.45%
65.57%
Cmax
100%
85.23%
117.33%
32.10%
120%
102.28%
140.79%
38.52%
140%
119.32%
164.26%
44.94%
150%
127.85%
175.99%
48.15%
160%
136.37%
187.73%
51.36%
180%
153.41%
211.19%
57.78%
200%
170.46%
234.66%
64.20%
These estimates are based on the assumption that within-participant standard deviations are 
0.193 and 0.189 for lnAUCinf and lnCmax, respectively, as obtained from Study B7981024.
Participants who discontinue from the study may be replaced at the sponsor’s discretion.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Not applicable.
10.1.3. Informed Consent Process
The investigator or the investigator’srepresentative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data. 
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant.
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A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 10 days from the previous ICD signature date.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
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responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents.
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality, such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
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10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes a source document and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (Pfizer CRU).
The investigator must maintain accurate documentation (source record) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or  
Pfizer-related information necessary for the appropriate scientific presentation or 
understanding of the study results. For joint publications, should there be disagreement 
regarding interpretation and/or presentation of specific analysis results, resolution of, and 
responsibility for, such disagreements will be the collective responsibility of all authors of 
the publication.
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For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.11. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the CTMS.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, and (c) site 
emergency phone number active 24 hours/day, 7 days per week.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant.
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values; for example: calculation of estimated kidney function (ie, 2021 
CKD-EPI eGFR). These additional tests would not require additional collection of blood. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
Table 8.
Protocol-Required Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea
Creatinine
Cystatin Ca
eGFR, eCrClb
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Creatinine kinase
Local dipstick:
pHc
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopyd and 
culturee
At screening:

FSHf

Urine drug screeningg

Hepatitis B surface 
antigen

Hepatitis B surface
antibody

Hepatits B core antibody

Hepatitis C antibody

Pregnancy test (β-hCG)h

Human 
immunodeficiency virus
At admission:

Urine drug screeningg

Pregnancy test (β-hCG)h
a.
Cystatin C (Scys): Screening or Baseline Scys is recommended to help differentiate post-baseline DIKI 
from DICI. Post-baseline, Scys is measured if and only if serum creatinine increase post-baseline is 
observed (see Section 7.1.1).
b.
Screening and Baseline eGFR or eCrCl is measured with Screat-based formula. Age-specific kidney 
function calculation (see Section 10.6.2) is recommended to assess presence or absence of post-baseline 
change in kidney function.
c.
Can be performed on dipstick or pH meter device.
d.
Only if dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
e.
Urinary culture only if deemed appropriate by the investigator.
f.
For confirmation of postmenopausal status only in females <60 years old and not using hormonal or 
HRT only.
g.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific).
h.
Local urine or serum testing will be used. See SoA for collection times and Section 8.3.6 for more 
details.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
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samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal test results that meet any of the conditions below must be recorded as 
an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the CT SAE Report Form or via PSSA to Pfizer Safety throughout 
the active collection period. These requirements are delineated for 3 types of events: 
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(1) SAEs; (2) nonserious AEs; and (3) exposure to the study intervention under study 
during pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form/PSSA for reporting of SAE information 
is not the same as the AE page of the CRF. When the same data are collected, the forms 
must be completed in a consistent manner. AEs should be recorded using concise 
medical terminology and the same AE term should be used on both the CRF and the CT 
SAE Report Form/PSSA for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form/PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding
All AEs/SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated SAE): is reported to Pfizer Safety using the CT SAE Report 
Form and EDP Supplemental Form or via PSSA. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form or PSSA, which would also 
include details of any SAE that might be associated with the EDB.
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form or via PSSA.

When an AE or SAE occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.
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
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.
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Assessment of Causality

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for 
marketed products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form/PSSA 
and in accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.
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Follow-Up of AEs and SAEs

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eg, eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is one of the methods to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.
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SAE Reporting to Pfizer Safety via the CT SAE Report Form

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom, and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak when having sexual intercourse with a WOCBP who is not 
currently pregnant.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study.
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Is a WOCBP and agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) during the intervention period and for at least 28 days/weeks after the 
last dose of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention(s). If a highly effective, 
user-dependent method is chosen, she agrees to concurrently use an effective barrier 
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method of contraception. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are co-administered, a barrier method or other nonhormonal method of contraception must 
also be used if the participant is using estradiol-containing contraceptives during the study 
treatment and until one menstrual cycle after stopping study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea or oligomenorrhea) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition:

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 
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
A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*

Intravaginal + barrier*

Transdermal + barrier*
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*

Injectable + barrier*
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Sexual Abstinence
8. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom, with or without spermicide;

Cervical cap, diaphragm or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm or sponge 
with spermicide (double-barrier methods).
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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of  ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, eosinophils (%), and alkaline phosphatase. Consideration should also be 
given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, total bile acids, liver imaging (eg, biliary tract), and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.6. Appendix 6: Kidney Safety: Monitoring Guidelines
10.6.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat 
measurement to estimate kidney function [Screat-based eGFR] or creatinine clearance 
[eCrCl]). Obtaining Screening or Baseline Scys and postbaseline reflex Scys (if confirmed 
Screat increase ≥0.3 mg/dL) makes it feasible to distinguish AKI from DICI. If Screat 
increase is confirmed after baseline, then reflex measurement of Scys is indicated (for adult 
and for pediatric participants):
ADULTS: Currently, 2021 CKD-EPI eGFR equations (Screat only-based and combined 
Screat plus Scys-based) are valid for use in adults only. At baseline Screat and Scys values 
are needed to calculate 2021 CKD-EPI eGFR by Screat only-based equation (see 
Table 10.6.2.1) and by combined Screat plus Scys-based equation. When post-baseline 
Screat increase ≥0.3 mg/dL is confirmed, then reflex Scys measurement is needed to enable 
post-baseline comparison of eGFR changes (Screat only-based eGFR and combined Screat 
plus Scys eGFR).
PEDIATRICS: Currently, no Screat plus Scys eGFR equations have been universally 
adopted for pediatrics. Therefore, comparison of baseline Screat and Scys to post-baseline 
Screat and reflex Scys are utilized to support differentiation of AKI from DIKI. Regardless 
of whether kidney function monitoring tests are required as a routine safety monitoring 
procedure in the study, if the investigator or sponsor deems it necessary to further assess 
kidney safety and quantify kidney function, then these test results should be managed and 
followed per standard of care.
10.6.2. Age-Specific Kidney Function Calculation Recommendations
10.6.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR (mL/min/1.73m²)32
2021 
CKD-EPI 
Screat Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
NA
eGFR = 143 × (Screat/0.7)-0.241 × (0.9938)Age
Female
if > 0.7
NA
eGFR = 143 × (Screat/0.7)-1.200 × (0.9938)Age
Male
if ≤ 0.9
NA
eGFR = 142 × (Screat/0.9)-0.302 × (0.9938)Age
Male
if > 0.9
NA
eGFR = 142 × (Screat/0.9)-1.200 × (0.9938)Age
2021 
CKD-EPI 
Screat-Scys 
Combined
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if ≤ 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age
Female
if > 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age
Male
if ≤ 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age
Male
if > 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age
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Male
if > 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age
10.6.3. Kidney Function Calculation Tools
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at Screening, Baseline, and post-Baseline visits. Site 
calculations of kidney function can be performed manually, using the age appropriate 
formulae (see Section 10.6.2) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error.
The United States National Kidney Foundation Online Calculators.

Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator
Investigational sites are responsible to ensure that the accurate age-specific equation is 
selected and that the correct units for serum creatinine (mg/dL only), serum cystatin C (mg/L 
only), total body weight (kg only), and age (years). Investigators are expected to (i) review 
and confirm correctness of the kidney function calculation results and (ii) evaluate the 
calculated value within the context of historical information available to them in the 
participant’s medical record. Investigators are responsible for the clinical oversight of the 
participant eligibility process, kidney function calculation, and dose selection and 
adjustments per study protocol. Investigators are encouraged to direct questions or 
uncertainties regarding kidney function and dosing to the Pfizer Clinical Team and Medical 
Monitor, if needed.
10.6.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AEgrading for decline in kidney function (ie, eGFR or eCrCl) will be according to Kidney 
Disease: Improving Global Outcomes (KDIGO) criteria.
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute).

New prolongation of QTcF by >60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF > 450 ms AND QTcF change from baseline >60 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex>120 ms).

New-onset right bundle branch block (QRS complex>120 ms).

Symptomatic bradycardia.

Asystole

In awake, symptom-free participants in sinus rhythm, with documented 
asystolic pauses ≥3 seconds or any escape rate <40 bpm, or with an escape 
rhythm that is below the AV node;

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.
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
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30-seconds duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The  major events of potential clinical concern listed above are recommended as “alerts” or notifications 
from the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-
inclusive of what is to reported as AEs/SAEs.
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10.8. Appendix 8: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
A1 to A3
albuminuria (KDIGO albuminuria severity standardization)
Abs
absolute
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the concentration-time curve from time 0 extrapolated to 
infinity
AUClast
area under the plasma concentration-time profile from time 0 to the 
time of the last quantifiable concentration (Clast)
AUCR
AUC in presence of Precipitant Drug/AUC in absence of Precipitant 
Drug
AV
atrioventricular
AxMP
auxiliary medicinal product
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
-hCG
-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology
CL/F
apparent clearance
Cmax
maximum observed concentration
Cmax,u
maximum unbound inhibitor concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
3CLpro
3C-like protease
CP-1
coproporphyrin I
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
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Abbreviation
Term
CTIS
Clinical Trial Information System
CYP
cytochrome P450
DCT
data collection tool
DDI
drug-drug interaction
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
19F-NMR
fluorine-19 nuclear magnetic resonance spectroscopy
F/U
follow-up
FIH
first in human
fm
fraction metabolized
FSH
follicle-stimulating hormone
fu,p
fraction unbound in human plasma
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDPE
high density polyethylene
HEK293
human embryonic kidney 293 cells 
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICD
informed consent document
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Abbreviation
Term
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ID
identification
Iin,max,u
maximal unbound inhibitor concentration in the hepatic inlet
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IV
Intravenous(ly)
KDIGO
Kidney Disease Improving Global Outcomes
Kel
elimination constant
Ki
inhibitor constant
LBBB
left bundle branch block
LFT
liver function test
MAD
multiple ascending dose
MDR
medical device regulation
Mpro
main protease
MQI
medically qualified individual
MRP2
multi-drug resistance protein 2
NA
not applicable
ND
not determined
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
NSAE
non-serious adverse event
NYHA 1
New York Heart Association Functioncal Classification 1
OAT3
organic anion transporter 3
OATP
organic anion transporting polypeptide
OATP1B1
organic anion transporting polypeptide 1B1
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PVC
premature ventricular contraction/complex
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
RB
blood-to-plasma ratio
RBC
red blood cell
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Scys
serum cystatin C
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Abbreviation
Term
Screat
serum creatinine
SmPC
Summary of Product Characteristics
SoA
schedule of activities
SOC
System Organ Class
SOP
standard operating procedure
SRSD
Single Reference Safety Document
STT
ST and T wave
SUSAR
Suspected Unexpected Serious Adverse Reaction
T bili
total bilirubin
t½
terminal half-life
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tlast
time of the last quantifiable concentration
Tmax
time for Cmax
ULN
upper limit of normal
US
United States
vs
versus
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WT
wildtype
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Fact Sheet For Healthcare Providers: Emergency Use Authorization For PaxlovidTM. 
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2
Paxlovid (nirmatrelvir+ritonavir) SmPC. EPAR - product information; 07 Mar 2023.
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3
Crestor (rosuvastatin calcium) SmPC. Product information; 09 Aug 2005: EMA. 
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4
Population Modeling Analysis Report (PMAR). PMAR-EQDD-C467a-DP4-1323. Chan
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Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. 
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Elsby R, Coghlan H, Edgerton J, et al. Mechanistic in vitro studies indicate that the 
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7
Karlgren M, Vildhede A, Norinder U, et al. Classification of inhibitors of hepatic 
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8
Annaert P, Ye ZW, Stieger B, et al. Interaction of HIV protease inhibitors with 
OATP1B1, 1B3, and 2B1. Xenobiotica. 2010 Mar 1;40(3):163-76.
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Pfeifer ND, Goss SL, Swift B, et al. Effect of Ritonavir on 99mTechnetium–Mebrofenin 
Disposition in Humans: A Semi‐PBPK Modeling and In Vitro Approach to Predict 
Transporter‐Mediated DDIs. CPT: Pharmacometrics & Systems Pharmacology. 2013 
Jan;2(1):e20.
                                                
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10
Shebley M, Liu J, Kavetskaia O, et al. Mechanisms and predictions of drug-drug 
interactions of the hepatitis C virus three direct-acting antiviral regimen: 
paritaprevir/ritonavir, ombitasvir, and dasabuvir. Drug Metabolism and Disposition. 
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Bierman WF, Scheffer GL, Schoonderwoerd A, et al. Protease inhibitors atazanavir, 
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12
Gupta A, Zhang Y, Unadkat JD, et al. HIV protease inhibitors are inhibitors but not 
substrates of the human breast cancer resistance protein (BCRP/ABCG2). Journal of 
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Martin PD, Warwick MJ, Dane A, et al. Metabolism, excretion, and pharmacokinetics of 
rosuvastatin in healthy adult male volunteers. Clin Ther, 2003. 25(11): p. 2822-35.
14
Martin PD, Warwick MJ, Dane AL, et al. Absolute oral bioavailability of rosuvastatin in 
healthy white adult male volunteers. Clin Ther, 2003. 25(10): p. 2553-63.
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Martin PD, Warwick MJ, Dane AL, et al. A double-blind, randomized, incomplete 
crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers. 
Clin Ther, 2003. 25(8): p. 2215-24.
16
Martin P, Gillen, M, Ritter, J, et al. Effects of Fostamatinib on the Pharmacokinetics of 
Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results 
From Phase I Clinical Studies. Drugs R D, 2016. 16(1): p. 93-107.
17
Cooper KJ, Martin PD, Dane AL, et al, Effect of itraconazole on the pharmacokinetics 
of rosuvastatin. Clinical Pharmacology & Therapeutics, 2003. 73(4): p. 322-9.
18
Stopfer P, Giessmann T, Hohl K, et al, Effects of Metformin and Furosemide on 
Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as 
Probe Drugs in a Transporter Cocktail. European Journal of Drug Metabolism and 
Pharmacokinetics, 2018. 43(1): p. 69-80.
19
Busti AJ, Bain AM, Hall RG, et al. Effects of atazanavir/ritonavir or 
fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. Journal of 
Cardiovascular Pharmacology. 2008 Jun 1;51(6):605-610.
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20
Samineni D, Desai PB, Sallans L, et al. Steady‐state pharmacokinetic interactions of 
darunavir/ritonavir with lipid‐lowering agent rosuvastatin. The Journal of Clinical 
Pharmacology. 2012 Jun;52(6):922-931.
21
Martin PD, Warwick MJ, Dane AL, et al. A double-blind, randomized, incomplete 
crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers. 
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22
Kimoto E, Costales C, West MA, et al. Biomarker-Informed Model-Based Risk 
Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug-Drug 
Interactions. Clinical Pharmacology & Therapeutics. 2022;111(2):404-415.
23
Kalluri HV, Kikuchi R, Coppola S, et al. Coproporphyrin I Can Serve as an Endogenous 
Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir 
Clinical Study. Clinical and Translational Science. 2021;14(1):373-381.
24
Lai Y, Mandlekar S, Shen H, et al. Coproporphyrins in Plasma and Urine Can Be 
Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by 
Organic Anion Transporting Polypeptide Inhibition. Journal of Pharmacology and 
Experimental Therapeutics. 2016;358(3):397-404.
25
Takehara I, Yoshikado T, Ishigame K, et al. Comparative Study of the 
Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and 
Endogenous Substrates in Healthy Volunteers. Pharmaceutical Research. 
2018;35(7):138.
26
Mori D, Kimoto E, Rago B, et al. Dose-Dependent Inhibition of OATP1B by 
Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers 
and OATP1B Probe Drugs. Clinical Pharmacology & Therapeutics. 
2020;107(4):1004-1013.
27
Kunze A, Ediage EN, Dillen L, et al. Clinical Investigation of Coproporphyrins as 
Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug-Drug 
Interactions. Clinical Pharmacokinetics. 2018;57(12):1559-1570.
28
Shen H, Christopher L, Lai Y, et al. Further Studies to Support the Use of 
Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for 
Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition. Drug 
Metabolism and Disposition. 2018;46(8):1075-1082.
29
LIVALO (pitavastatin). United States Prescribing Information (USPI); September 2020
Available from: 
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https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022363s018lbl.pdf. 
Accessed: 23 Feb 2023.
30
Feng S, Bo Q, Coleman HA, et al. Further Evaluation of Coproporphyrins as Clinical 
Endogenous Markers for OATP1B. Journal of Clinical Pharmacology. 
2021;61(8):1027-1034.
31
Mori D, Kashihara Y, Yoshikado T, et al. Effect of OATP1B1 genotypes on plasma 
concentrations of endogenous OATP1B1 substrates and drugs, and their association in 
healthy volunteers. Drug Metabolism and Pharmacokinetics. 2019;34(1):78-86.
32
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. New England Journal of Medicine. 
2021;385(19):1737-1749.
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SAP_001.pdf: 
Protocol C4671052 (PF-07321332) Statistical Analysis Plan
DMB02-GSOP-RF02 7.0 Statistical Analysis Plan Template 31-Jan-2022
PFIZER CONFIDENTIAL
TMF Doc ID: 98.03
Page 1 of 16
Protocol C4671052
A Phase 1, Randomized, Fixed Sequence, Multiple-Dose, Open-Label Study
to Estimate the Effect of Nirmatrelvir (PF-07321332)/Ritonavir on Rosuvastatin
Pharmacokinetics in Healthy Adult Participants
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
26 May 2023
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Modifications to the Analysis Plan Described in the Protocol..................................5
2.2. Study Objectives and Endpoints ...............................................................................5
2.3. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoints.....................................................................................................7
3.2. Secondary Endpoints.................................................................................................7
3.2.1. Other PK parameters of rosuvastatin............................................................7
3.2.2. Safety data ....................................................................................................7
3.3. Baseline Variables.....................................................................................................8
3.4. Other Endpoint ..........................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................8
3.5.2. Laboratory Data............................................................................................8
3.5.3. Vital Signs ....................................................................................................8
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................9
5.1. Hypotheses and Decision Rules ................................................................................9
5.2. General Methods .......................................................................................................9
5.2.1. Analyses for Binary/Categorical Endpoints .................................................9
5.2.2. Analyses for Continuous Endpoints .............................................................9
5.3. Methods to Manage Missing Data ..........................................................................10
5.3.1. Pharmacokinetic Data.................................................................................10
5.3.2. Safety Data..................................................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................11
6.1. Primary Endpoints...................................................................................................11
6.2. Secondary Endpoints...............................................................................................11
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6.2.1. Other PK parameters of rosuvastatin..........................................................11
6.2.2. Safety data ..................................................................................................13
6.2.3. Other Endpoint............................................................................................13
6.3. Subset Analyses.......................................................................................................13
6.4. Baseline and Other Summaries and Analyses.........................................................13
6.4.1. Demographic Summaries............................................................................13
6.4.2. Study Conduct and Participant Disposition................................................13
6.4.3. Study Treatment Exposure .........................................................................13
6.4.4. Concomitant Medications and Nondrug Treatments..................................13
6.5. Safety Summaries and Analyses .............................................................................13
6.5.1. Adverse Events...........................................................................................14
6.5.2. Laboratory Data..........................................................................................14
6.5.3. Vital Signs ..................................................................................................14
7. INTERIM ANALYSES.......................................................................................................14
APPENDICES .........................................................................................................................15
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LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
Table 2.
Treatment Sequence....................................................................................6
Table 3.
Definitions of PK Parameters.....................................................................7
Table 4.
PK Parameters to be Summarized Descriptively by Treatment ...............12
APPENDICES
Appendix 1. SAS Code for Analyses.......................................................................................15
Appendix 2. List of Abbreviations...........................................................................................16
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NOTE: Italicized text within this document has been taken verbatim from the Protocol.
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol 
Amendment
Rationale
Specific Changes
1 /
26 May 2023
Original 
03 Apr 2023
N/A
N/A
2. INTRODUCTION
Nirmatrelvir is a potent and selective inhibitor of the SARS-CoV-2 Mpro that was developed
for the treatment of COVID-19. Ritonavir is a strong CYP3A4 inhibitor being used to inhibit
the metabolism of nirmatrelvir in order to increase plasma concentrations of nirmatrelvir to
values that are efficacious.
The purpose of the study is to assess the effect of nirmatrelvir/ritonavir on the plasma PK of
rosuvastatin, a sensitive OATP1B1 substrate. Both nirmatrelvir and ritonavir have the
potential to inhibit OATP1B1. Rosuvastatin is considered a well-known sensitive substrate of 
OATP1B1 and is likely to be a concomitant medication in patients who have COVID-19 and 
are prescribed nirmatrelvir/ritonavir. Therefore, this study will assess the impact of
nirmatrelvir/ritonavir on the pharmacokinetics of rosuvastatin.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4671052.
2.1. Modifications to the Analysis Plan Described in the Protocol
None.
2.2. Study Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To assess the effect of multiple doses of 
nirmatrelvir/ritonavir on the plasma 
pharmacokinetics of a single, oral dose of
rosuvastatin in healthy participants.

AUCinf, Cmax of rosuvastatin.
Secondary: 
Secondary: 

To further characterize the plasma 
pharmacokinetics of a single, oral dose of 
rosuvastatin administered with
nirmatrelvir/ritonavir.

AUClast, Tmax, t½, CL/F, and Vz/F of rosuvastatin.
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Objectives
Endpoints

To evaluate the safety and tolerability of a
single oral dose of rosuvastatin when co-
administered with nirmatrelvir/ritonavir.

Vital signs, laboratory tests and adverse events.
2.3. Study Design
This is a Phase 1, randomized, fixed sequence, multiple-dose, open-label study of the effect of 
nirmatrelvir/ritonavir on rosuvastatin PK in healthy adult participants.
A total of approximately 12 healthy male and/or female participants will be enrolled in the
study. Participants who discontinue from the study may be replaced at the sponsor’s
discretion. Participants will be screened within 28 days prior to the first dose of 
investigational product. Participants will report to the CRU the day prior to Day 1 dosing 
(i.e., Day -1) in Period 1. Participants will remain in the CRU for a total of 11 days and 10 
nights (including Period 1 and Period 2). To adequately remove any drug effects of 
rosuvastatin from Period 1 to Period 2, there will be a minimum 5-day washout period 
between the 2 rosuvastatin dosing events. The total rosuvastatin PK will then be assessed 
over 72 hours.
Participants will receive 2 treatments across 2 periods, as outlined in Table 2 below:
Table 2.
Treatment Sequence
Sequence
Period 1
Washout
Period 2
Sequence 1 (N = 12)
Treatment A
At least 5 days between
the 2 rosuvastatin dosing
events
Treatment B
N = number of enrolled participants.

Treatment A (rosuvastatin, Reference): Single oral administration of rosuvastatin 10 mg
tablet on Day 1 in the morning (AM dose).

Treatment B (rosuvastatin + nirmatrelvir/ritonavir, Test): Nirmatrelvir/ritonavir 300 mg 
(2 × 150 mg)/100 mg tablets q12h (BID) for 2 days (Day 1 morning [AM] and evening 
[PM] and Day 2 morning [AM], 3 doses total) with a single oral administration of 
rosuvastatin 10 mg tablet on Day 2 in the morning (AM dose). Nirmatrelvir and ritonavir 
will be dosed within no more than 5 minutes of each other. Rosuvastatin single dose will
be dosed within 5 minutes after the Day 2 morning (AM) nirmatrelvir/ritonavir dose.
The expected duration of participants from Screening to the follow-up telephone contact will 
be approximately 11 weeks.
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
The primary endpoints are the plasma AUCinf (if data permit, otherwise AUClast) and Cmax of 
rosuvastatin. The test/reference ratios for AUCinf (if data permit, otherwise AUClast) and Cmax
will be derived with Treatment B (rosuvastatin + nirmatrelvir/ritonavir) as the test treatment 
and Treatment A (rosuvastatin) as the reference treatment.
Plasma PK parameters of rosuvastatin will be derived (as data permit) from the
concentration-time data using standard noncompartmental methods as outlined in the 
Table 3. Actual PK sampling times will be used in the derivation of rosuvastatin PK
parameters when available. In the case that actual PK sampling times are not available,
nominal PK sampling time will be used in the derivation of PK parameters.
Table 3.
Definitions of PK Parameters
Parameter
Definition
Method of Determination
AUCinf*
Area under the concentration-time curve 
from time 0 extrapolated to infinity.
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable time point 
from the log-linear regression analysis.
AUClast**
Area under the plasma concentration-time 
profile from time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method.
Cmax
Maximum observed concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
t½*
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the 
loglinear concentration-time curve. Only those 
data points judged to describe the terminal 
loglinear decline will be used in the regression.
CL/F*
Apparent clearance
Dose/AUCinf
Vz/F*
Apparent volume of distribution
Dose/(AUCinf • kel)
*If data permit.
**Tlast will also be included in order to provide additional context for AUClast. Tlast will only be listed, not 
summarized.
3.2. Secondary Endpoints
3.2.1. Other PK parameters of rosuvastatin
The secondary endpoints include other plasma PK parameters of rosuvastatin such as 
AUClast, Tmax, t1/2, CL/F and Vz/F.
3.2.2. Safety data
Other secondary endpoints are the safety and tolerability data, discussed in Section 3.5.
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3.3. Baseline Variables
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 
3.4. Other Endpoint
One predose blood sample for PK analysis of nirmatrelvir/ritonavir will be collected on 
Period 2 Day 2.
3.5. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection
days, baseline assessment, and list of parameters):

adverse events (AE)

laboratory data

vital signs data
3.5.1. Adverse Events
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 35 days after the last dose of study intervention will be counted as treatment emergent 
and attributed to the last treatment taken. The time period for collecting AEs (“active 
collection period”) for each participant begins from the time the participant provides 
informed consent.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol. To determine if there 
are any clinically significant laboratory abnormalities, the haematological, clinical chemistry 
(serum) and urinalysis safety tests will be assessed against the criteria specified in the 
sponsor reporting standards. The assessment will not take into account whether each 
participant’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter.
For both periods, the baseline measurement is the predose measurement on Period 1 Day -1.
Changes from baseline will be defined as the change between the postdose and baseline 
measurements.
3.5.3. Vital Signs
Supine blood pressure (BP), pulse rate (PR) and temperature will be measured at times 
specified in the SoA given in the protocol.
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For both periods, the baseline measurement is the predose measurement on Day 1 in each 
period. Changes from baseline will be defined as the change between the postdose and 
baseline measurements.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
Participant Analysis Set
Description
Enrolled/Randomly
assigned to study
intervention
"Enrolled" means a participant's, or their legally authorized
representative’s, agreement to participate in a clinical study
following completion of the informed consent process and
screening.
Safety Analysis Set
All participants who take at least 1 dose of study intervention.
Participants will be analyzed according to the product they
actually received.
PK Concentration Set
All participants who take at least 1 dose of study intervention
and in whom at least 1 concentration value is reported.
PK Parameter Set
All participants who take at least 1 dose of study intervention
and in whom at least 1 of the PK parameters of primary
interest are reported.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analysis will be performed after study participant data set release following last 
participant last visit.
5.1. Hypotheses and Decision Rules
No statistical hypothesis will be tested in this study.
5.2. General Methods
5.2.1. Analyses for Binary/Categorical Endpoints
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS).
5.2.2. Analyses for Continuous Endpoints
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized.
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5.3. Methods to Manage Missing Data
5.3.1. Pharmacokinetic Data
Methods to handle missing PK data are described below. 
Concentrations Below the Limit of Quantification:
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. In listings, BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.
Deviations, Missing Concentrations and Anomalous Values:
In summary tables and plots of median profiles, statistics will be calculated having set
concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (i.e., not done) or NS (i.e., no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst.
PK Parameters:
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as NC 
(i.e., not calculated). (Note that NC values will not be generated beyond the day that a 
participant discontinues).
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC. For statistical analyses, PK parameters coded as NC will also 
be set to missing.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to a dosing error or an unexpected event such as vomiting before all the compound is 
adequately absorbed from the gastrointestinal tract), this will be footnoted in summary tables 
and will not be included in the calculation of summary statistics or statistical analyses.  For 
instance, if a participant has a vomiting event post dose that is within a duration of time that 
is 2-times the derived median Tmax for the population for the administered treatment, then the 
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pharmacokineticist should consider the exclusion of the PK concentration data collected 
following the initial vomiting event in that treatment period and the PK parameter data 
reported for that treatment period from the datasets used to calculate summary statistics or 
statistical analyses.
5.3.2. Safety Data
Missing values in standard summaries of safety data will be imputed according to CaPS.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
Plasma AUCinf (if data permit, otherwise AUClast) and Cmax of rosuvastatin will be 
summarized by treatment group and will include the set of summary statistics as specified in
Table 4.
For the evaluation of the effect of multiple doses of nirmatrelvir/ritonavir on the PK of 
rosuvastatin, natural log transformed AUCinf (if data permit), AUClast and Cmax will be 
analyzed using a mixed effect model with treatment as a fixed effect and participant as a 
random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The adjusted mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of adjusted 
geometric means (Test/Reference) and 90% CI for the ratios. Treatment A (rosuvastatin) will 
be the Reference treatment while Treatment B (rosuvastatin + nirmatrelvir/ritonavir) will be 
the Test treatment.
For AUCinf, AUClast and Cmax, a listing of the individual participant ratios (Test/Reference) 
will be provided. Box and whisker plots for AUCinf, AUClast and Cmax will be plotted by 
treatment and overlaid with geometric means.
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers then the effect of these on the conclusions will be investigated through 
alternative transformations and/or analyses excluding outliers. Justification for any 
alternative to the planned analysis will be given in the report of the study.
6.2. Secondary Endpoints
6.2.1. Other PK parameters of rosuvastatin
Secondary endpoints include other PK parameters of rosuvastatin such as AUClast, Tmax, t1/2, 
CL/F and Vz/F. The PK parameters will be listed and summarized descriptively by treatment 
group in accordance with Pfizer data standards on the PK Parameter Set, as data permit. 
Missing values will be handled as detailed in Section 5.3.1. Each PK parameter will be 
summarized by treatment group and will include the set of summary statistics as specified in
Table 4. 
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Table 4.
PK Parameters to be Summarized Descriptively by Treatment 
Parameter
Summary Statistics
AUCinf, AUClast, Cmax, 
CL/F, Vz/F
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV
Tmax
N, median, minimum, maximum
t½
N, arithmetic mean, median, SD, %CV, minimum, maximum
Supporting data from the estimation of t½ and AUCinf will be listed by analyte and group:
terminal phase rate constant (kel); goodness of fit statistic from the log-linear regression (r2);
the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, and number of
time points used in the estimation of kel. This data may be included in the clinical study
report.
PK Concentrations:
The plasma concentrations will be listed and descriptively summarized by nominal PK 
sampling time and treatment. Individual participant, as well as mean and median profiles of 
the plasma concentration-time data will be plotted by treatment using actual (for individual) 
and nominal (for mean and median) times, respectively. Mean and median profiles will be 
presented on both linear and semi-log scales.
Presentations of concentrations will include:

A listing of all concentrations sorted by participant ID, treatment and nominal time
postdose. The concentration listing will also include the actual times. Deviations from the 
nominal time will be given in a separate listing.

A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ.

Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by treatment (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose).

Individual concentration-time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment per 
scale).
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
Individual concentration-time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant (containing 
all treatments) per scale].
CP-1 samples will be collected for exploratory research of CP-1 as an endogenous 
biomarker for OATP1B1 inhibition, according to the SoA as specified in the protocol. CP-1 
biomarker data will be listed and descriptively summarized by nominal sampling time and by 
treatment.
6.2.2. Safety data
Analyses and summaries of safety data are described in Section 6.5.
6.2.3. Other Endpoint
The plasma concentration of nirmatrelvir/ritonavir collected on Period 2 Day 2 will be listed 
by nominal and actual times.
6.3. Subset Analyses
There are no planned subset analyses.
6.4. Baseline and Other Summaries and Analyses
6.4.1. Demographic Summaries
Demographic characteristics will be summarized for enrolled population in accordance with 
the CaPS.
6.4.2. Study Conduct and Participant Disposition
Participant evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the CaPS.
6.4.3. Study Treatment Exposure
Study treatment exposure will be listed.
6.4.4. Concomitant Medications and Nondrug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be reported in 
the listings.
6.5. Safety Summaries and Analyses
All safety analyses will be performed on the Safety Analysis Set.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
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6.5.1. Adverse Events
AEs will be reported in accordance with the CaPS.
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS.
6.5.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the CaPS.
6.5.3. Vital Signs
Vital sign data will be listed and summarized by treatment in accordance with the CaPS.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. As this is an open-label 
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development.
Final analysis will follow the official database release.  As this will be an open-label study, 
there is no formal unblinding of the randomization code.
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APPENDICES
Appendix 1. SAS Code for Analyses
An example of the PROC MIXED code is provided below:
For the primary objective:
proc mixed data=tab.pk;
class trt participant;
model l&var=trt/ ddfm=KR;
random participant /subject=participant;
lsmeans trt;
estimate 'B vs A' trt -1 1  /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows
Treatment A: rosuvastatin (Reference)
Treatment B: rosuvastatin + nirmatrelvir/ritonavir (Test)
*/
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Appendix 2. List of Abbreviations
Abbreviation
Term
%CV
coefficient of variation
AE
adverse event
AUCextrap%
the percent of AUCinf based on extrapolation
AUCinf
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time
AUClast
area under the plasma concentration-time profile from time zero to the 
time of the last quantifiable concentration
BID
twice daily
BLQ
below the limit of quantitation
BP
blood pressure
CaPS
Clinical Data Interchange Standards Consortium and Pfizer Standards
CI
confidence interval
Clast
last quantifiable concentration
CL/F
apparent clearance after oral dose
Cmax
maximum plasma concentration
COVID-19
coronavirus disease 2019
CP-1
coproporphyrin I
CRU
Clinical research unit
CSR
clinical study report
CYP3A4
cytochrome P450 3A4
ECG
electrocardiogram
kel
terminal phase rate constant
LLQ
lower limit of quantitation
mg
milligram
Mpro
main protease
N/A
not applicable
NC
not calculated
ND
not done
NS
no sample
OATP1B1
organic anion transporting polypeptide 1B1
PK
pharmacokinetic(s)
PR
pulse rate
r2
goodness of fit statistic from the log-linear regression
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SoA
schedule of activities
t½
terminal elimination half-life
TEAE
treatment emergent adverse event
Tmax
time for Cmax
Vz/F
apparent volume of distribution after oral dose
090177e19da372ec\Approved\Approved On: 05-Jun-2023 15:46 (GMT)