Drug-Drug Interaction Study to Estimate the Effect of PF-07321332/Ritonavir and Ritonavir on Midazolam in Healthy Participants

Healthy Participants Clinical Trial

Official title:

COVID-19: A PHASE 1, OPEN-LABEL, 3-TREATMENT, 6-SEQUENCE, 3-PERIOD CROSSOVER STUDY TO ESTIMATE THE EFFECT OF PF-07321332/RITONAVIR AND RITONAVIR ON THE PHARMACOKINETICS OF MIDAZOLAM IN HEALTHY PARTICIPANTS.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05032950
• Other study ID #: C4671013
• Secondary ID: 2021-003590-62
• Status: Completed
• Phase: Phase 1
• Start date: September 17, 2021
• Est. completion date: December 9, 2021

Study information

• Verified date: December 2022
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to estimate the effect PF-07321332/Ritonavir and Ritonavir on Midazolam (a cytochrome P450 [CYP]3A4 substrate) in Healthy Adult Participants.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: December 9, 2021
• Est. primary completion date: December 9, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Female participants of childbearing potential must have a negative (urine or serum) pregnancy test.

2. Body mass index (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 New York Heart Association (NYHA) 1, underlying structural heart disease, Wolff Parkinson-White syndrome).

4. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).

5. History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or hepatitis C virus (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.

Related Conditions & MeSH terms

• Healthy Participants

Intervention

Drug:
• Midazolam
Midazolam administered as a single dose on Day 1
• PF-07321332/ritonavir + Midazolam
PF-07321332/ritonavir: Administered orally every 12 hours for a total of 9 doses on Days 1-5 Midazolam: Administered orally as a single dose on Day 5
• Ritonavir + Midazolam
Ritonavir: Administered orally every 12 hours for a total of 9 doses on Day1-5. Midazolam: Administered orally as a single dose on Day 5

Locations

Country	Name	City	State
Belgium	Brussels Clinical Research Unit	Brussels	Bruxelles-capitale, Région DE

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir	Cmax for midazolam following single dose administration with and without PF-07321332/ritonavir was observed directly from data. Natural log-transformed Cmax for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Primary	Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinity Time (AUCinf) of Midazolam When Administered Alone and With PF-07321332/Ritonavir	AUCinf for midazolam following single dose administration with and without PF-07321332/ritonavir was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. Natural log-transformed AUCinf for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Primary	Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (Clast) (AUClast) of Midazolam When Administered Alone and With PF-07321332/Ritonavir	AUClast for midazolam following single dose administration with and without PF-07321332/ritonavir was calculated by Linear/Log trapezoidal method. Natural log-transformed AUClast for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (PF-07321332/ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event was considered a TEAE if the event started during the effective duration of treatment. All events that start on or after the first dosing day and time/ start time, if collected, but before the last dose plus the lag time (28 days) were flagged as TEAEs. The algorithm did consider any events that started prior to the first dose date. Any events occurring following start of treatment or increasing in severity were counted as treatment emergent. Events that occur in a non-treatment period (for example, Washout or Follow-up) were counted as treatment emergent and attributed to the previous treatment taken.	Baseline up to Day 28
Secondary	Number of Participants With Laboratory Abnormalities	The haematological, clinical chemistry (serum) and urinalysis safety tests were assessed against the criteria specified in the sponsor reporting standards to determine if there were any clinically significant laboratory abnormalities. The assessment took into account whether each participant's baseline test result was within or outside the laboratory reference range for the particular laboratory parameter. Baseline was defined as the last planned predose measurement taken in each study period.	Baseline up to Day 28
Secondary	Number of Participants With Vital Signs Abnormalities	Baseline was the last predose recording in each study period. Only post baseline values are included in this analysis	Baseline up to Day 28
Secondary	Number of Participants With Electrocardiogram (ECG) Abnormalities	Baseline and changes from baseline in PR, QT, QRS, heart rate and QTcF were summarized by treatment and time postdose. Baseline was defined as the average of the triplicate predose recordings in each study period. ECG endpoints and changes from baseline (QTcF, PR, QRS), over all measurements taken postdose, were also summarized descriptively by treatment using categories as defined in the Criteria for Safety Values of Potential Clinical Concern appendix of the protocol and for QTc values corresponding to ICH E14 thresholds, which are: QTcF (msec): 450	Baseline up to Day 28
Secondary	Cmax of Midazolam When Administered Alone and With Ritonavir	Cmax for midazolam following single dose administration with and without ritonavir was observed directly form data. Natural log-transformed Cmax for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Secondary	AUCinf of Midazolam When Administered Alone and With Ritonavir	AUCinf for midazolam following single dose administration with and without ritonavir was calculated by AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis. Natural log-transformed AUCinf for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Secondary	AUClast of Midazolam When Administered Alone and With Ritonavir	AUClast for midazolam following single dose administration with and without ritonavir was calculated by Linear/Log trapezoidal method. Natural log-transformed AUClast for Midazolam were analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The ratios (ritonavir + midazolam [test]/midazolam [reference] and 90% CIs) were expressed as percentages.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam/ritonavir: Day 5 pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose
Secondary	Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir	CL/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/AUCinf.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Secondary	Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir	Vz/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/(AUCinf • kel).	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Secondary	Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir	Tmax for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by observed directly from data as time of first occurrence.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose
Secondary	Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir	t½ for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Loge(2)/kel, where kel was 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.	Midazolam: Day 1 Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 hours postdose; Midazolam+PF-07321332/ritonavir: Day 5 predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours postdose

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