Renal Impairment Study of PF-07321332 Boosted With Ritonavir in Adult Participants With Renal Impairment and in Healthy Participants With Normal Renal Function.

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1, non-randomized, open-label, 2-part study to investigate the effect of renal impairment on the pharmacokinetics (PK), safety and tolerability of a single oral dose of PF-07321332 in combination with the PK boosting agent ritonavir. Participants will be selected and categorized into normal renal function or renal impairment groups based on their estimated glomerular filtration rate. Part 1: will be conducted in approximately 24 participants (approximately 8 per group) with stable mild or moderate renal impairment and a control group of participants with normal renal function. Part 2 will be conducted in approximately 8 participants with stable severe renal impairment.

Official Title
-----------------
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL STUDY TO ASSESS THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF PF-07321332 BOOSTED WITH RITONAVIR IN ADULT PARTICIPANTS WITH RENAL IMPAIRMENT AND IN HEALTHY PARTICIPANTS WITH NORMAL RENAL FUNCTION.

Conditions
-----------------
Renal Impairment

Intervention / Treatment
-----------------
* Drug: PF-07321332/ritonavir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, non-smoker and/or light smoker Have a diagnosis of stable renal impairment Meet the following estimated glomerular filtration rate (eGFR) criteria during the screening period (based on 2 Screening visits) based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: Mild renal impairment: eGFR between 60 - 89 mL/min. Moderate renal impairment: eGFR ≥30 mL/min and <60 mL/min. Severe renal impairment: eGFR <30 mL/min, but not requiring hemodialysis. Normal renal function: eGFR ≥90 mL/min Renal impairment participants: Any form of renal impairment except acute nephritic syndrome (participants with history of previous nephritic syndrome but in remission can be included). Good general health commensurate with the population with chronic kidney disease (renal impairment). Stable concomitant drug regimen for the management of individual participant's medical conditions, so long as they are considered necessary for the welfare of the study participants (eg, standard therapy for underlying diseases), and are not contraindicated with study drug, and are unlikely to interfere with the PK of study drug. Healthy participants with normal renal function: No clinically relevant abnormalities identified by a detailed medical history, full physical examination, including temperature, blood pressure (BP) and pulse rate measurement, 12 lead ECG and clinical laboratory tests. Demographically comparable to the group of participants with impaired renal function. Each participant's body weight within ±15 kg of the mean body weight of renal impairment group. Each participant's age within ±10 years of the mean age of the renal impairment group. Exclusion Criteria: Positive test result for SARS-CoV-2 infection at the time of screening or Day -1. History of HIV infection, hepatitis B, or hepatitis C; positive testing at screening for HIV, HBsAg, HBcAb, or HCVAb. As an exception a positive HBsAb test due to Hepatitis B vaccination is allowed. Renal transplant recipients. Urinary incontinence without catheterization Any condition possibly affecting drug absorption (eg, prior bariatric surgery, gastrectomy, cholecystectomy, appendectomy). Participants who have been vaccinated with COVID-19 vaccines within the past 2 weeks of dosing, or are to be vaccinated with these vaccines at any time during the study. A positive urine drug test, for illicit drugs, at Screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >2 × upper limit of normal (ULN) Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is≤ ULN. History of sensitivity reactions to ritonavir or any of the formulation components of PF 07321332 or ritonavir. Female participants of childbearing potential who are unwilling or unable to use highly effective methods of contraception as outlined in Section 5.3.4 for the duration of the study and for at least 28 days after the administration of investigational product, pregnant female participants, female participants planning to become pregnant during the duration of the study until 28 days after the administration of investigational product, breastfeeding female participants. Renal impairment participants: Participants requiring hemodialysis and/or peritoneal dialysis Participants with other clinically significant disease that may affect the safety of the participant or that may affect the PK of PF-07321332. Participants with any significant hepatic, cardiac, or pulmonary disease or participants who are clinically nephrotic. Healthy participants with normal renal function: 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). Screening supine BP >140 mm Hg (systolic) or >90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is >140 mm Hg (systolic) or >90 mm Hg (diastolic), 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07321332<br>PF 07321332/ritonavir | Drug: PF-07321332/ritonavir<br>* PF-07321332 in combination with the PK boosting agent, ritonavir, being developed for the treatment of COVID-19<br>* Other names: PF-07321332;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of PF-07321332 |  | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 
| Area Under the Plasma Concentration-time Profile From Time Zero (0) to Extrapolated Infinite Time (AUCinf) of PF-07321332 | AUCinf was calculated by AUClast + (Clast/kel). AUClast was the area under the plasma concentration-time profile from time 0 to the time of Clast. Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 
| Amount of PF-07321332 Excreted Unchanged in Urine Over 48 Hours (Ae48) | Total amount of unchanged drug excreted in the urine over 48 hours. | Part 1 and Part 2: 0 to 48 hours post dose on Day 1 | 
| Renal Clearance (CLr) of PF-07321332 | Renal clearance was calculated as total amount of unchanged drug excreted in the urine over 48 hours (Ae48) divided by area under the plasma concentration-time profile from time 0 to 48 hours post dose. | Part 1 and Part 2: 0 to 48 hours post dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (SAEs), Treatment Emergent Treatment Related AEs and Treatment Emergent Treatment Related SAEs | An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that, at any dose resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was a suspected transmission via a Pfizer product of an infectious agent was considered serious; other important medical events. TEAEs were events occurred following start of treatment or increased in severity up to maximum of 35 days after last dose. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. Relatedness was judged by investigator. | Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days) | 
| Number of Participants With Clinical Laboratory Abnormalities | The hematology, clinical chemistry and urinalysis tests were included in the laboratory examination. The criteria for hematology evaluation included hemoglobin less than (<) 0.8*lower limit of normal (LLN), hematocrit <0.8*LLN, erythrocytes <0.8*LLN, erythrocyte mean corpuscular hemoglobin <0.9*LLN and lymphocytes <0.8*LLN. The criteria for clinical chemistry evaluation included neutrophils <0.8*LLN, eosinophils greater than (>) 1.2* upper limit of normal (ULN), monocytes >1.2*ULN, urea nitrogen >1.3*ULN, creatinine >1.3*ULN, urate >1.2*ULN, potassium >1.1*ULN and bicarbonate <0.9*LLN. The criteria for urinalysis evaluation included thyrotropin >1.2*ULN, glucose >1.5*ULN, fibrinogen >1.25*baseline, ketones greater than or equal to (>=) 1, urine protein >=1, nitrite >=1 and leukocyte esterase >=1. | Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days) | 
| Number of Participants With Clinically Significant Vital Signs Abnormalities | Supine blood pressure, pulse rate, respiratory rate and oral temperature were evaluated in vital signs examination. Clinical significance was judged by investigator. | Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days) | 
| Number of Participants With Clinically Significant Findings in Physical Examination | A complete physical examination included, at a minimum, head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and neurological systems. Clinical significance was judged by investigator. | Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days) | 
| Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | A standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) were collected using an ECG machine that automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS complex. All scheduled ECGs were performed after the participant had rested quietly for at least 5 minutes in a supine position. Clinical significance was judged by investigator. | Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days) | 
| Plasma Concentration of PF-07321332 at 12 Hours Post Dose (C12) |  | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 | 
| Plasma Concentration of PF-07321332 at 24 Hours Post Dose (C24) |  | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose on Day 1 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07321332 | Tmax was observed directly from data as time of first occurrence. | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 
| Area Under the Plasma Concentration-time Profile From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUClast) of PF-07321332 | Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration was determined by linear/log trapezoidal method. | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 
| Apparent Clearance (CL/F) of PF-07321332 From Plasma | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the plasma. CL/F was calculated by Dose/AUCinf. | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 
| Apparent Volume of Distribution (Vz/F) of PF-07321332 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. Vz/F was calculated by dose/(AUCinf*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 
| Terminal Elimination Plasma Half-life (t1/2) of PF-07321332 | t1/2 was calculated by Loge(2)/kel. kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Part 1 and Part 2: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-dose on Day 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2, COVID-19