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

Phase 1

Completed

Conditions: Healthy Participant

Interventions: Drug: PF-07321332/ritonavir
Drug: Carbamazepine
Drug: PF 07321332/ritonavir

Registration Number: NCT04962230

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Period 2	PF 07321332/ritonavir	Carbamazepine + PF-07321332/ritonavir orally.
Period 1	PF-07321332/ritonavir	PF-07321332/ritonavir orally as a single dose
Period 2	Carbamazepine	Carbamazepine + PF-07321332/ritonavir orally.

Primary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of PF-07321332	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	Cmax was defined as maximum observed plasma concentration and can be observed directly from data.
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of PF-07321332	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 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.

Secondary Outcome Measures

Name	Time	Method
Terminal Half-Life ( t1/2) of PF-07321332	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 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.
Number of Participants With Laboratory Abnormalities	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	Safety laboratory assessments included hematology, urinalysis, and clinical chemistry. All the safety laboratory samples were collected following at least a 4 hour fast.
Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings	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	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.
Apparent Volume of Distribution (Vz/F) of PF-07321332	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 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.
Cmax of Ritonavir	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	Cmax was defined as maximum observed plasma concentration and can be observed directly from data.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	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	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.
Apparent Oral Clearance (CL/F) of PF-07321332	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 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.
AUCinf of Ritonavir	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 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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	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)	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.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07321332	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 was defined as time to reach maximum observed plasma concentration and can be observed directly from data as time of first occurrence.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-07321332	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 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.
AUClast of Ritonavir	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 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.
Tmax of Ritonavir	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 was defined as time to reach maximum observed plasma concentration and can be observed directly from data as time of first occurrence.
CL/F of Ritonavir	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 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.
t1/2 of Ritonavir	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 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.
Vz/F of Ritonavir	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 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.