Drug-Drug Interaction Study Assessing Effect of Carbamazepine on PF-07321332 Boosted With Ritonavir

Study Overview
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Brief Summary
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This is a drug-drug interaction study to assess the effects of a single dose of PF-07321332/ritonavir after multiple dose administrations of carbamazepine. Pharmacokinetic (PK) will be evaluated for PF-07321332 and ritonavir. Carbamazepine is being utilized as a cytochrome P450 3A4 (CYP3A4) inducer.

Official Title
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A PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD CROSSOVER STUDY TO ESTIMATE THE EFFECT OF CARBAMAZEPINE ON THE PHARMACOKINETICS OF PF-07321332 BOOSTED WITH RITONAVIR IN HEALTHY PARTICIPANTS

Conditions
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Healthy Participant

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female participants of childbearing potential must have a negative (urine or serum) pregnancy test. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). Exclusion Criteria: Positive test reverse-transcriptase polymerase chain reaction (RT-PCR) result for SARS-CoV-2 infection at the time of Screening or Day -1. Subjects shown to carry or be positive for human leukocyte antigen (HLA)-B*1502 and HLA-A*3101 Participants taking monoamine oxidase inhibitors (MAOIs) should discontinue MAOI for a minimum of 14 days prior to dosing in the current study. Hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, vaginal ring, and postcoital contraceptive methods) and hormone replacement therapy must have been discontinued at least 28 days prior to the first dose of investigational product. Depo Provera must be discontinued at least 6 months prior to the first dose of study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a Phase 1, fixed sequence, 2-period study to estimate the effect of a strong CYP3A4 inducer, carbamazepine, on the PK of PF-07321332 and ritonavir in healthy participants. A total of approximately 12 healthy male and/or female participants will be enrolled into the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Period 1<br>PF-07321332/ritonavir orally as a single dose | Drug: PF-07321332/ritonavir<br>* PF-07321332/ritonavir administered orally as a single dose on Day 1, Period 1<br>|
| Experimental: Period 2<br>Carbamazepine + PF-07321332/ritonavir orally. | Drug: Carbamazepine<br>* In Period 2, Days 1-3, participants will receive low-dose of carbamazepine twice daily (BID), then a titrated mid-dose of carbamazepine BID on Days 4-7, and finally maintaining carbamazepine at the high-dose on Days 8-15.<br>Drug: PF 07321332/ritonavir<br>* In Period 2, Day 14, participants will receive a single dose of PF-07321332/ritonavir orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of PF-07321332 | Cmax was defined as maximum observed plasma concentration and can be observed directly from data. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-07321332 | AUCinf was defined as area under the concentration-time curve from time 0 to infinity and was calculated as AUClast + (Clast*/kel), where Clast* is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Ritonavir | Cmax was defined as maximum observed plasma concentration and can be observed directly from data. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| AUCinf of Ritonavir | AUCinf was defined as area under the concentration-time curve from time 0 to infinity and was calculated as AUClast + (Clast*/kel), where Clast* is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An Adverse event (AE) was any untoward medical occurrence in a participant. A serious AE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity, congenital anomaly/birth. An AE was considered treatment-emergent AE (TEAE) if the event occurred during the on-treatment period. A treatment-related AE was any untoward medical occurrence attributed to the study drug in a participant who received study drug. A treatment-related SAE was a treatment-related AE and was defined as any untoward medical occurrence at any dose that: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Relatedness to study drug was assessed by the investigator. | Screening up to Day 3 in Period 1; Day 1 up to 35 days from administration of the final dose of study intervention or early termination/discontinuation in Period 2 (maximum of approximately 12 weeks) | 
| Number of Participants With Laboratory Abnormalities | Safety laboratory assessments included hematology, urinalysis, and clinical chemistry. All the safety laboratory samples were collected following at least a 4 hour fast. | Screening, Day -1 prior to dosing, and Day 2 in Period 1; Days 3, 6, 9, 12, 16 or early termination/discontinuation in Period 2 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital signs including single supine blood pressure and pulse rate were performed following at least a 5 minute rest in a supine position. Blood pressure (BP) and pulse rate (PR) assessments were performed after collection of electrocardiograms (ECGs) and prior to collection of blood draws if planned together. Respiratory rate (RR) was also evaluated. | Screening and Day 1 pre-dose, and at 1.5, 8, and 24 hours post dose in Period 1; Days 2, 3, 4, 6, 8, 10, 12, Day 14 pre-dose, and at 1.5, 8, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | All ECG assessments (triplicate) were made after at least a 10 minute rest in a supine position and prior to any blood draws or vital sign measurements. | Screening and Day 1 pre-dose, and at 1.5, 8, and 24 hours post dose in Period 1; Days 2, 3, 4, Day 14 pre-dose, and at 1.5, 8, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07321332 | Tmax was defined as time to reach maximum observed plasma concentration and can be observed directly from data as time of first occurrence. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-07321332 | AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of last observed quantifiable plasma concentration (Clast) and was determined by Linear/Log trapezoidal method. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Apparent Oral Clearance (CL/F) of PF-07321332 | CL/F was defined as apparent clearance. 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 oral clearance) is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F is calculated as dose/AUCinf. AUCinf = area under the plasma concentration versus time curve from time zero extrapolated to infinite time. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Apparent Volume of Distribution (Vz/F) of PF-07321332 | Vz/F was defined as apparent volume of distribution. Vz/F is calculated as Dose/(AUCinf * kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Terminal Half-Life ( t1/2) of PF-07321332 | t1/2 was defined as the time measured for the plasma concentration of drug to decrease by one half. t1/2 is calculated as Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline was used in the regression. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Tmax of Ritonavir | Tmax was defined as time to reach maximum observed plasma concentration and can be observed directly from data as time of first occurrence. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| AUClast of Ritonavir | AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of Clast and was determined by Linear/Log trapezoidal method. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| CL/F of Ritonavir | CL/F was defined as apparent clearance. 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 oral clearance) is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F is calculated as dose/AUCinf. AUCinf = area under the plasma concentration versus time curve from time zero extrapolated to infinite time. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| Vz/F of Ritonavir | Vz/F was defined as apparent volume of distribution. Vz/F is calculated as Dose/(AUCinf * kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 
| t1/2 of Ritonavir | t1/2 was defined as the time measured for the plasma concentration of drug to decrease by one half. t1/2 is calculated as Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Only those data points judged to describe the terminal log-linear decline was used in the regression. | Day 1 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post dose in Period 1; Day 14 pre-dose, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours post-dose or early termination/discontinuation in Period 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug-drug interaction, Carbamazepine, CYP3A4 inducer