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

NCT05032950 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C46710132021-003590-62
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy Participants

Keywords

Drug-drug interaction; Midazolam; COVID-19 (Coronavirus disease 2019); SARS-CoV (severe acute respiratory syndrome coronavirus)

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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 Outcomes (11)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  Baseline up to Day 28

• Number of Participants With Laboratory Abnormalities

  Baseline up to Day 28

• Number of Participants With Vital Signs Abnormalities

  Baseline up to Day 28

• Number of Participants With Electrocardiogram (ECG) Abnormalities

  Baseline up to Day 28

• Cmax of Midazolam When Administered Alone and With Ritonavir

  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

Study Arms (3)

Treatment A

ACTIVE COMPARATOR

Midazolam orally

Drug: Midazolam

Treatment B

EXPERIMENTAL

PF-07321332/ritonavir orally + Midazolam orally

Drug: PF-07321332/ritonavir + Midazolam

Treatment C

ACTIVE COMPARATOR

Ritonavir orally + Midazolam orally

Drug: Ritonavir + Midazolam

Interventions

Midazolam DRUG

Midazolam administered as a single dose on Day 1

Treatment A

PF-07321332/ritonavir + Midazolam DRUG

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

Treatment B

Ritonavir + Midazolam DRUG

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

Treatment C

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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 New York Heart Association (NYHA) 1, underlying structural heart disease, Wolff Parkinson-White syndrome).
• Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
• 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.
• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (1)

Brussels Clinical Research Unit

Brussels, Bruxelles-capitale, Région de, B-1070, Belgium

Location

Related Publications (2)

• Cox DS, Rehman M, Khan T, Ginman K, Salageanu J, LaBadie RR, Wan K, Damle B. Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants. Br J Clin Pharmacol. 2023 Nov;89(11):3352-3363. doi: 10.1111/bcp.15835. Epub 2023 Jul 12.

  PMID: 37354048 DERIVED

• Sagawa K, Lin J, Jaini R, Di L. Physiologically-Based Pharmacokinetic Modeling of PAXLOVID with First-Order Absorption Kinetics. Pharm Res. 2023 Aug;40(8):1927-1938. doi: 10.1007/s11095-023-03538-5. Epub 2023 May 25.

  PMID: 37231296 DERIVED

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

COVID-19; Severe Acute Respiratory Syndrome

Interventions

Midazolam; nirmatrelvir; Ritonavir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a Phase I, crossover, 3-treatment, 6-sequence study to evaluate the effect of PF-07321332/ritonavir and ritonavir on the PK of midazolam in healthy participants. Midazolam is a substrate for CYP3A4. A total of approximately 12 healthy male and/or female participants will be enrolled into the study.

Study Record Dates

• First Submitted: August 27, 2021
• First Posted: September 2, 2021
• Study Start: September 17, 2021
• Primary Completion: December 9, 2021
• Study Completion: December 9, 2021
• Last Updated: October 4, 2023
• Results First Posted: October 4, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)