Drug-Drug Interaction Study Assessing Effect of Itraconazole on PF-07321332/Ritonavir in Healthy Participants

Study Overview
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Brief Summary
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The purpose of this study is to estimate the effect of a strong inhibitor of CYP3A4 (itraconazole) on the pharmacokinetics (PK) of PF-07321332/ritonavir in healthy participants.

Official Title
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COVID-19: A PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD CROSSOVER STUDY TO ESTIMATE THE EFFECT OF ITRACONAZOLE ON THE PHARMACOKINETICS OF PF-07321332/RITONAVIR IN HEALTHY PARTICIPANTS

Conditions
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Healthy Participant

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants who are overtly healthy as determined by medical evaluation including medical history, PE, laboratory tests, vital signs and standard 12 lead ECGs. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. Female participants must have a negative pregnancy test. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). - Exclusion Criteria: Positive test result for SARS-CoV-2 infection at the time of Screening or Day -1. 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). 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 NYHA 1, underlying structural heart disease, Wolff Parkinson-White syndrome). Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality or other conditions or situations related to COVID-19 pandemic (eg, contact with positive case, residence, or travel to an area with high incidence) that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.

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 I, fixed sequence, 2-period study to evaluate the effect of the strong CYP3A4 inhibitor, itraconazole, on the PK of PF-07321332 and ritonavir in healthy participants. A total of 12 healthy participants will be enrolled into this study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Period 1<br>PF-07321332/ritonavir orally | Drug: PF-07321332/ritonavir<br>* Administered orally every 12 hours for days for a total of 5 doses from Day 1 through Day 3<br>|
| Experimental: Period 2<br>Itraconazole + PF-07321332/ritonavir orally. | Drug: Itraconazole<br>* Administered orally once daily for 8 days from Days 1 through 8<br>Drug: PF-07321332/ritonavir<br>* Administered orally BID for 3 day for a total on 5 doses starting on Day 4 through Day 6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) of PF-07321332 | The Cmax of PF-07321332 in the study was observed directly from data. | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2. | 
| Area Under the Plasma Concentration-time Profile From Time Zero to Time Tau (τ), Where Tau=12-hour Dosing Interval(AUCtau) for PF-07321332 | The AUCtau of PF-07321332 was determined by Linear/Log trapezoidal method. | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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; resulted in congenital anomaly/birth, was a suspected transmission via a Pfizer product of an infectious agent,pathogenic or non-pathogenic, was considered serious. The focus of AE summaries was on treatment-emergent AE (TEAE). An AE was considered TEAE if the event occurred during the on-treatment period. | Screening up to Day 35 | 
| Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality) | Safety laboratory assessments included urinalysis, hematology, chemistry and other. All the safety laboratory samples were collected following at least a 4-hour fast. | Screening up to Day 9 of Period 2 or Early termination/discontinuation. | 
| Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings | Triplicate 12-lead ECG readings approximately 2 minutes apart were taken at each test. All ECG assessments were made after at least a 5-minute rest in a supine position and prior to any blood draws or vital sign measurements. | Screening up to Day 9 of Period 2 or Early termination/discontinuation. | 
| Change From Baseline in Vital Signs Data - Supine Systolic Blood Pressure | Vital signs(systolic and diastolic blood pressure, and pulse rate) were measured with participants after having a rest for at least 5 minutes in a supine position. Vital signs assessment were performed after collection of ECGs and prior to collection of blood draws if scheduled at the same time. | Screening up to Day 9 of Period 2 or Early termination/discontinuation. | 
| Change From Baseline in Vital Signs Data - Supine Diastolic Blood Pressure | Vital signs(systolic and diastolic blood pressure, and pulse rate) were measured with participants after having a rest for at least 5 minutes in a supine position. Vital signs assessment were performed after collection of ECGs and prior to collection of blood draws if scheduled at the same time. | Screening up to Day 9 of Period 2 or Early termination/discontinuation. | 
| Change From Baseline in Vital Signs Data - Supine Pulse Rate | Vital signs(systolic and diastolic blood pressure, and pulse rate) were measured with participants after having a rest for at least 5 minutes in a supine position. Vital signs assessment were performed after collection of ECGs and prior to collection of blood draws if scheduled at the same time. | Screening up to Day 9 of Period 2 or Early termination/discontinuation. | 
| Time for Cmax (Tmax) for PF-07321332 | PF-07321332 Tmax was observed directed from data | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2 | 
| Terminal Half-life(t1/2) of PF-07321332 | Terminal half-life was defined as the time measured for the plasma concentration of drug to decrease by one half. | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2 | 
| Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration(AUClast) of PF-07321332 | AUClast of PF-07321332 was determined by Linear/Log trapezoidal method. | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2. | 
| Apparent Clearance(CL/F) of PF-07321332 | CL/F was apparent clearance. | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2. | 
| Apparent Volume of Distribution (Vz/F) of PF-07321332 | Vz/F was apparent volume of distribution. | Days 1, 2, 3 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose on Day 3) in Period 1; Days 1, 4, 5, 6 (pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, and 72 hours postdose on Day 6) of Period 2. | 

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