Clinical trial NCT04909853: Renal Impairment Study of PF-07321332 Boosted With Ritonavir in Adult Participants With Renal Impairment and in Healthy Participants With Normal Renal Function.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Keywords: SARS-CoV-2
COVID-19
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2021-06-02
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


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.

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of PF-07321332
timeFrame: 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
measure: Area Under the Plasma Concentration-time Profile From Time Zero (0) to Extrapolated Infinite Time (AUCinf) of PF-07321332
timeFrame: 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
measure: Amount of PF-07321332 Excreted Unchanged in Urine Over 48 Hours (Ae48)
timeFrame: Part 1 and Part 2: 0 to 48 hours post dose on Day 1
measure: Renal Clearance (CLr) of PF-07321332
timeFrame: Part 1 and Part 2: 0 to 48 hours post dose on Day 1
Secondary outcomes:
measure: 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
timeFrame: Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days)
measure: Number of Participants With Clinical Laboratory Abnormalities
timeFrame: Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days)
measure: Number of Participants With Clinically Significant Vital Signs Abnormalities
timeFrame: Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days)
measure: Number of Participants With Clinically Significant Findings in Physical Examination
timeFrame: Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days)
measure: Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
timeFrame: Part 1 and Part 2: Day -1 up to maximum of 35 days after last dose (maximum of 38 days)
measure: Plasma Concentration of PF-07321332 at 12 Hours Post Dose (C12)
timeFrame: 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
measure: Plasma Concentration of PF-07321332 at 24 Hours Post Dose (C24)
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07321332
timeFrame: 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
measure: Area Under the Plasma Concentration-time Profile From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUClast) of PF-07321332
timeFrame: 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
measure: Apparent Clearance (CL/F) of PF-07321332 From Plasma
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) of PF-07321332
timeFrame: 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
measure: Terminal Elimination Plasma Half-life (t1/2) of PF-07321332
timeFrame: 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
Other outcomes:
Locations:
city: Tustin
country: United States
facility: Orange County Research Center
state: California
city: Miami
country: United States
facility: Investigational Drug Services (IDS) University of Miami Hospitals and Clinics
state: Florida
city: Miami
country: United States
facility: University of Miami Division of Clinical Pharmacology
state: Florida
city: Tampa
country: United States
facility: Genesis Clinical Research, LLC
state: Florida
city: Saint Paul
country: United States
facility: Prism Research LLC dba Nucleus Network
state: Minnesota
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Toussi SS, Neutel JM, Navarro J, Preston RA, Shi H, Kavetska O, LaBadie RR, Binks M, Chan PLS, Demers N, Corrigan B, Damle B. Pharmacokinetics of Oral Nirmatrelvir/Ritonavir, a Protease Inhibitor for Treatment of COVID-19, in Subjects With Renal Impairment. Clin Pharmacol Ther. 2022 Oct;112(4):892-900. doi: 10.1002/cpt.2688. Epub 2022 Jul 5.