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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04962022

Enrollment

Registered

2021-07-14

Start date

2021-07-20

Completion date

2021-09-30

Last updated

2023-07-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Participant

Keywords

Drug-drug interaction, Itraconazole, CYP3A4 inhibitor

Brief summary

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.

Interventions

DRUGPF-07321332/ritonavir

Administered orally every 12 hours for days for a total of 5 doses from Day 1 through Day 3

DRUGItraconazole

Administered orally once daily for 8 days from Days 1 through 8

Study design

Allocation

NON_RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

NONE

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

Yes

Inclusion criteria

1. 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. 2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures. 3. Female participants must have a negative pregnancy test. 4. BMI of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb). -

Exclusion criteria

1. Positive test result for SARS-CoV-2 infection at the time of Screening or Day -1. 2. 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). 3. 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). 4. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). 5. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. 6. 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.

Design outcomes

Primary

Measure	Time frame	Description
Maximum Observed Concentration (Cmax) of PF-07321332	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.	The Cmax of PF-07321332 in the study was observed directly from data.
Area Under the Plasma Concentration-time Profile From Time Zero to Time Tau (τ), Where Tau=12-hour Dosing Interval(AUCtau) for PF-07321332	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.	The AUCtau of PF-07321332 was determined by Linear/Log trapezoidal method.

Secondary

Measure	Time frame	Description
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)	Screening up to Day 9 of Period 2 or Early termination/discontinuation.	Safety laboratory assessments included urinalysis, hematology, chemistry and other. All the safety laboratory samples were collected following at least a 4-hour fast.
Change From Baseline in Vital Signs Data - Supine Systolic Blood Pressure	Screening up to Day 9 of Period 2 or Early termination/discontinuation.	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.
Change From Baseline in Vital Signs Data - Supine Diastolic Blood Pressure	Screening up to Day 9 of Period 2 or Early termination/discontinuation.	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.
Change From Baseline in Vital Signs Data - Supine Pulse Rate	Screening up to Day 9 of Period 2 or Early termination/discontinuation.	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.
Number of Participants With Clinically Significant 12-lead Electrocardiogram (ECG) Findings	Screening up to Day 9 of Period 2 or Early termination/discontinuation.	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.
Terminal Half-life(t1/2) of PF-07321332	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 was defined as the time measured for the plasma concentration of drug to decrease by one half.
Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration(AUClast) of PF-07321332	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.	AUClast of PF-07321332 was determined by Linear/Log trapezoidal method.
Apparent Clearance(CL/F) of PF-07321332	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.	CL/F was apparent clearance.
Apparent Volume of Distribution (Vz/F) of PF-07321332	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.	Vz/F was apparent volume of distribution.
Time for Cmax (Tmax) for PF-07321332	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	PF-07321332 Tmax was observed directed from data
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Screening up to Day 35	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.

Countries

Belgium

Participant flow

Pre-assignment details

This was a 2-period,fixed-sequence crossover study. A total of 12 participants were assigned to and received the treatment in period 1. One participant discontinued due to withdrawal. The remaining 11 participants completed Period 1 and continued to receive the treatment in Period 2 and all completed Period 2.

Participants by arm

Arm	Count
Overall Study All participants who received PF-07321332 (suspension)/ritonavir 300/100 mg, Itraconazole 200 mg and PF-07321332(suspension)/ritonavir 300/100 mg in Period 1 and 2, respectively.	12
Total	12

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Overall Study
Age, Customized 18-25 years	0 Participants
Age, Customized <18 years	0 Participants
Age, Customized 26-35 years	5 Participants
Age, Customized 36-45 years	3 Participants
Age, Customized >45 years	4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	10 Participants
Sex: Female, Male Female	1 Participants
Sex: Female, Male Male	11 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 11
other Total, other adverse events	7 / 12	10 / 11
serious Total, serious adverse events	0 / 12	0 / 11

Outcome results

Primary

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.

Time frame: 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.

Population: The analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of interest were reported.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-07321332 (Suspension)/Ritonavir 300/100 mg BID, Fasted	Area Under the Plasma Concentration-time Profile From Time Zero to Time Tau (τ), Where Tau=12-hour Dosing Interval(AUCtau) for PF-07321332	33350 ng*hr/mL	Geometric Coefficient of Variation 20
Itraconazole 200 mg QD + PF-07321332(Suspension)/Ritonavir 300/100 mg BID, Fasted	Area Under the Plasma Concentration-time Profile From Time Zero to Time Tau (τ), Where Tau=12-hour Dosing Interval(AUCtau) for PF-07321332	46290 ng*hr/mL	Geometric Coefficient of Variation 18

p-value: 0.0590% CI: [129.25, 149.11]Mixed Models Analysis

Primary

Maximum Observed Concentration (Cmax) of PF-07321332

The Cmax of PF-07321332 in the study was observed directly from data.

Population: The analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 concentration value was reported.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-07321332 (Suspension)/Ritonavir 300/100 mg BID, Fasted	Maximum Observed Concentration (Cmax) of PF-07321332	4678 ng/mL	Geometric Coefficient of Variation 17
Itraconazole 200 mg QD + PF-07321332(Suspension)/Ritonavir 300/100 mg BID, Fasted	Maximum Observed Concentration (Cmax) of PF-07321332	5546 ng/mL	Geometric Coefficient of Variation 15

p-value: 0.0590% CI: [112.5, 124.97]Mixed Models Analysis

Secondary

Apparent Clearance(CL/F) of PF-07321332

CL/F was apparent clearance.

Population: The analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of interest were reported.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-07321332 (Suspension)/Ritonavir 300/100 mg BID, Fasted	Apparent Clearance(CL/F) of PF-07321332	8.990 L/hr	Geometric Coefficient of Variation 20
Itraconazole 200 mg QD + PF-07321332(Suspension)/Ritonavir 300/100 mg BID, Fasted	Apparent Clearance(CL/F) of PF-07321332	6.478 L/hr	Geometric Coefficient of Variation 18

Secondary

Apparent Volume of Distribution (Vz/F) of PF-07321332

Vz/F was apparent volume of distribution.

Population: The analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of interest were reported. Here, Number of Participants analyzed signifies number of participants evaluable for this outcome measure.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-07321332 (Suspension)/Ritonavir 300/100 mg BID, Fasted	Apparent Volume of Distribution (Vz/F) of PF-07321332	104.7 L	Geometric Coefficient of Variation 33
Itraconazole 200 mg QD + PF-07321332(Suspension)/Ritonavir 300/100 mg BID, Fasted	Apparent Volume of Distribution (Vz/F) of PF-07321332	72.07 L	Geometric Coefficient of Variation 16

Secondary

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.

Population: The analysis population included all participants who took at least 1 dose of study intervention and in whom at least 1 of the PK parameters of interest were reported.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
PF-07321332 (Suspension)/Ritonavir 300/100 mg BID, Fasted	Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration(AUClast) of PF-07321332	41840 ng*hr/mL	Geometric Coefficient of Variation 21
Itraconazole 200 mg QD + PF-07321332(Suspension)/Ritonavir 300/100 mg BID, Fasted	Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration(AUClast) of PF-07321332	74430 ng*hr/mL	Geometric Coefficient of Variation 21

Secondary

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.

Time frame: Screening up to Day 9 of Period 2 or Early termination/discontinuation.