Healthy Participants
Conditions
Keywords
Drug-drug interaction, Midazolam, COVID-19 (Coronavirus disease 2019), SARS-CoV (severe acute respiratory syndrome coronavirus)
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.
Interventions
DRUGMidazolam
Midazolam administered as a single dose on Day 1
DRUGPF-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
DRUGRitonavir + 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
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | 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 | 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. |
| 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 | 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 | 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. |
| 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline up to Day 28 | 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\<value≤480; 480\<value≤500; \>500; QTcF (msec) increase from baseline: 30\<change≤60; change\>60 |
| 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 | 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. |
| AUCinf 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 | 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. |
| AUClast 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 pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline up to Day 28 | 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. |
| Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 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 | Vz/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/(AUCinf • kel). |
| Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 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 | 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. |
| Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 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 | 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. |
| Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 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 | CL/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/AUCinf. |
| Number of Participants With Laboratory Abnormalities | Baseline up to Day 28 | 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. |
| Number of Participants With Vital Signs Abnormalities | Baseline up to Day 28 | Baseline was the last predose recording in each study period. Only post baseline values are included in this analysis |
Countries
Belgium
Participant flow
Pre-assignment details
A total of 12 healthy participants were randomized to receive midazolam, PF-07321332/ritonavir + midazolam, and ritonavir + midazolam in a total of 6 sequences.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants enrolled in this study | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous Mean (SD) | 34.6 Years STANDARD_DEVIATION 9.26 |
| Age, Customized 18-25 Years | 2 Participants |
| Age, Customized <18 Years | 0 Participants |
| Age, Customized 26-35 Years | 4 Participants |
| Age, Customized 36-45 Years | 4 Participants |
| Age, Customized >45 Years | 2 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 10 Participants |
| Race/Ethnicity, Customized White | 9 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 | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 4 / 10 | 9 / 11 | 7 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 11 |
Outcome results
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | 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 | 26.13 ng*hr/mL | Geometric Coefficient of Variation 45 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | 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 | 363.9 ng*hr/mL | Geometric Coefficient of Variation 13 |
Comparison: Natural log-transformed AUCinf of midazolam was analyzed using mixed effect model with treatment, period and sequence as fixed effects and participant in sequence as random effect. Estimates of the adjusted mean differences (AMD) (Test-Reference) and 90%CIs were obtained from the model. The AMD and 90%CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90%CI for the ratios.90% CI: [1204.54, 1697.71]Mixed Models Analysis
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | 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 | 25.02 ng*hr/mL | Geometric Coefficient of Variation 44 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | 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 | 353.8 ng*hr/mL | Geometric Coefficient of Variation 13 |
Comparison: Natural log-transformed AUClast of midazolam was analyzed using mixed effect model with treatment, period and sequence as fixed effects and participant in sequence as random effect. Estimates of the adjusted mean differences (AMD) (Test-Reference) and 90%CIs were obtained from the model. The AMD and 90%CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90%CI for the ratios.90% CI: [1224.42, 1721.35]Mixed Models Analysis
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | 9.812 ng/mL | Geometric Coefficient of Variation 38 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir | 36.18 ng/mL | Geometric Coefficient of Variation 17 |
Comparison: Natural log-transformed Cmax of midazolam was analyzed using mixed effect model with treatment, period and sequence as fixed effects and participant in sequence as random effect. Estimates of the adjusted mean differences (AMD) (Test-Reference) and 90%CIs were obtained from the model. The AMD and 90%CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90%CI for the ratios.90% CI: [318.91, 425.41]Mixed Models Analysis
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 76.57 Litre/hour | Geometric Coefficient of Variation 45 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 5.500 Litre/hour | Geometric Coefficient of Variation 13 |
| Ritonavir 100 mg + Midazolam 2 mg | Apparent Clearance (CL/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 4.776 Litre/hour | Geometric Coefficient of Variation 15 |
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).
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 488.6 Litre | Geometric Coefficient of Variation 48 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 79.84 Litre | Geometric Coefficient of Variation 28 |
| Ritonavir 100 mg + Midazolam 2 mg | Apparent Volume of Distribution (Vz/F) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 76.43 Litre | Geometric Coefficient of Variation 31 |
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | AUCinf of Midazolam When Administered Alone and With Ritonavir | 26.13 ng*hr/mL | Geometric Coefficient of Variation 45 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | AUCinf of Midazolam When Administered Alone and With Ritonavir | 418.6 ng*hr/mL | Geometric Coefficient of Variation 15 |
Comparison: Natural log-transformed AUCinf of midazolam was analyzed using mixed effect model with treatment, period and sequence as fixed effects and participant in sequence as random effect. Estimates of the adjusted mean differences (AMD)(Test-Reference) and 90%CIs were obtained from the model. The AMD and 90%CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90%CI for the ratios90% CI: [1385.75, 1953.11]Mixed Models Analysis
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | AUClast of Midazolam When Administered Alone and With Ritonavir | 25.02 ng*hr/mL | Geometric Coefficient of Variation 44 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | AUClast of Midazolam When Administered Alone and With Ritonavir | 408.8 ng*hr/mL | Geometric Coefficient of Variation 15 |
Comparison: Natural log-transformed AUClast of midazolam was analyzed using mixed effect model with treatment, period and sequence as fixed effects and participant in sequence as random effect. Estimates of the adjusted mean differences (AMD)(Test-Reference) and 90%CIs were obtained from the model. The AMD and 90%CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90%CI for the ratios.90% CI: [1414.59, 1988.69]Mixed Models Analysis
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | Cmax of Midazolam When Administered Alone and With Ritonavir | 9.812 ng/mL | Geometric Coefficient of Variation 38 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Cmax of Midazolam When Administered Alone and With Ritonavir | 38.03 ng/mL | Geometric Coefficient of Variation 18 |
Comparison: Natural log-transformed Cmax of midazolam was analyzed using mixed effect model with treatment, period and sequence as fixed effects and participant in sequence as random effect. Estimates of the adjusted mean differences (AMD)(Test-Reference) and 90%CIs were obtained from the model. The AMD and 90%CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90%CI for the ratios.90% CI: [335.25, 447.21]Mixed Models Analysis
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\<value≤480; 480\<value≤500; \>500; QTcF (msec) increase from baseline: 30\<change≤60; change\>60
Time frame: Baseline up to Day 28
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS DURATION, AGGREGATE (MSEC) - %Change≥50% | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - Change>60 | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 480<Value≤500 | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 450<Value≤480 | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR INTERVAL, AGGREGATE (MSEC) - Value≥300 | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 30<Change≤60 | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS DURATION, AGGREGATE (MSEC) - Value≥140 | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR INTERVAL, AGGREGATE (MSEC) - %Change≥25/50% | 0 Participants |
| Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - Value>500 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 450<Value≤480 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR INTERVAL, AGGREGATE (MSEC) - Value≥300 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR INTERVAL, AGGREGATE (MSEC) - %Change≥25/50% | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS DURATION, AGGREGATE (MSEC) - Value≥140 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS DURATION, AGGREGATE (MSEC) - %Change≥50% | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 480<Value≤500 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - Value>500 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 30<Change≤60 | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - Change>60 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS DURATION, AGGREGATE (MSEC) - Value≥140 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR INTERVAL, AGGREGATE (MSEC) - Value≥300 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - Value>500 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | PR INTERVAL, AGGREGATE (MSEC) - %Change≥25/50% | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - Change>60 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 450<Value≤480 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QRS DURATION, AGGREGATE (MSEC) - %Change≥50% | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 30<Change≤60 | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTCF INTERVAL, AGGREGATE (MSEC) - 480<Value≤500 | 0 Participants |
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.
Time frame: Baseline up to Day 28
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | URINALYSIS - URINE Hemoglobin (Scalar) ≥1 | 2 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Lymphocytes/Leukocytes (%) >1.2x ULN | 0 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Neutrophils (10^3/mm^3) <0.8x LLN | 0 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Neutrophils/Leukocytes (%) <0.8x LLN | 0 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Eosinophils/Leukocytes (%) >1.2x ULN | 0 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Monocytes/Leukocytes (%) >1.2x ULN | 1 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Prothrombin Time (sec) >1.1x ULN | 0 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY - Thyrotropin (uIU/mL) <0.8x LLN | 1 Participants |
| Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY - Fibrinogen (mg/dL) >1.25x Baseline | 1 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Monocytes/Leukocytes (%) >1.2x ULN | 1 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | URINALYSIS - URINE Hemoglobin (Scalar) ≥1 | 1 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Lymphocytes/Leukocytes (%) >1.2x ULN | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Eosinophils/Leukocytes (%) >1.2x ULN | 1 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY - Thyrotropin (uIU/mL) <0.8x LLN | 1 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Neutrophils (10^3/mm^3) <0.8x LLN | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY - Fibrinogen (mg/dL) >1.25x Baseline | 1 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Prothrombin Time (sec) >1.1x ULN | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Neutrophils/Leukocytes (%) <0.8x LLN | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Prothrombin Time (sec) >1.1x ULN | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | URINALYSIS - URINE Hemoglobin (Scalar) ≥1 | 3 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Eosinophils/Leukocytes (%) >1.2x ULN | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Monocytes/Leukocytes (%) >1.2x ULN | 2 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY - Fibrinogen (mg/dL) >1.25x Baseline | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Neutrophils/Leukocytes (%) <0.8x LLN | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Lymphocytes/Leukocytes (%) >1.2x ULN | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | HEMATOLOGY - Neutrophils (10^3/mm^3) <0.8x LLN | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Laboratory Abnormalities | CLINICAL CHEMISTRY - Thyrotropin (uIU/mL) <0.8x LLN | 1 Participants |
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.
Time frame: Baseline up to Day 28
Population: All participants randomly assigned to study intervention and who take at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events (All Causalities) | 4 Participants |
| Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events (Treatment related) | 4 Participants |
| Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with serious adverse events | 0 Participants |
| Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with severe adverse events | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with severe adverse events | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events (All Causalities) | 9 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with serious adverse events | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events (Treatment related) | 9 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with severe adverse events | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events (Treatment related) | 7 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with serious adverse events | 0 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with adverse events (All Causalities) | 7 Participants |
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
Time frame: Baseline up to Day 28
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Midazolam 2 mg | Number of Participants With Vital Signs Abnormalities | 0 Participants |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Vital Signs Abnormalities | 1 Participants |
| Ritonavir 100 mg + Midazolam 2 mg | Number of Participants With Vital Signs Abnormalities | 0 Participants |
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam 2 mg | Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 4.988 Hour | Standard Deviation 2.2058 |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 10.47 Hour | Standard Deviation 2.9096 |
| Ritonavir 100 mg + Midazolam 2 mg | Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 11.54 Hour | Standard Deviation 3.4741 |
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.
Time frame: 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
Population: The PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Midazolam 2 mg | Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 1.00 Hour |
| PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg | Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 1.00 Hour |
| Ritonavir 100 mg + Midazolam 2 mg | Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir | 1.02 Hour |