Trial Outcomes & Findings for Drug-Drug Interaction Study to Estimate the Effect of PF-07321332/Ritonavir and Ritonavir on Midazolam in Healthy Participants (NCT NCT05032950)
NCT ID: NCT05032950
Last Updated: 2023-10-04
Results Overview
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.
COMPLETED
PHASE1
12 participants
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
2023-10-04
Participant Flow
A total of 12 healthy participants were randomized to receive midazolam, PF-07321332/ritonavir + midazolam, and ritonavir + midazolam in a total of 6 sequences.
Participant milestones
| Measure |
Treatment Sequence 1
Period 1: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 2: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
Treatment Sequence 2
Period 1: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 3: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
Treatment Sequence 3
Period 1: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
|
Treatment Sequence 4
Period 1: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment A: Midazolam Single dose of 2 mg midazolam administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
|
Treatment Sequence 5
Period 1: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 3: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
Treatment Sequence 6
Period 1: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 2: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|---|---|---|
|
Overall Study
STARTED
|
2
|
2
|
2
|
2
|
2
|
2
|
|
Overall Study
COMPLETED
|
2
|
2
|
1
|
1
|
2
|
2
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
1
|
1
|
0
|
0
|
Reasons for withdrawal
| Measure |
Treatment Sequence 1
Period 1: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 2: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
Treatment Sequence 2
Period 1: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 3: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
Treatment Sequence 3
Period 1: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
|
Treatment Sequence 4
Period 1: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment A: Midazolam Single dose of 2 mg midazolam administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
|
Treatment Sequence 5
Period 1: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 2: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 3: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
Treatment Sequence 6
Period 1: Treatment A: Midazolam Single dose of 2 mg midazolam was administered orally on Day 1, followed by serial PK sampling and 2-day washout (Duration: Day 1 to Day 3).
Period 2: Treatment C: Ritonavir + Midazolam Ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
Period 3: Treatment B: PF-07321332/Ritonavir + Midazolam PF-07321332 300 mg/ritonavir 100 mg was administered orally every 12 hours for a total of 9 doses on Days 1-5 and a single oral dose of midazolam 2 mg was administered on Day 5 followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|---|---|---|
|
Overall Study
Adverse Event
|
0
|
0
|
1
|
1
|
0
|
0
|
Baseline Characteristics
Drug-Drug Interaction Study to Estimate the Effect of PF-07321332/Ritonavir and Ritonavir on Midazolam in Healthy Participants
Baseline characteristics by cohort
| Measure |
All Participants
n=12 Participants
All participants enrolled in this study
|
|---|---|
|
Age, Continuous
Mean (SD)
|
34.6 Years
STANDARD_DEVIATION 9.26 • n=93 Participants
|
|
Age, Customized
<18 Years
|
0 Participants
n=93 Participants
|
|
Age, Customized
18-25 Years
|
2 Participants
n=93 Participants
|
|
Age, Customized
26-35 Years
|
4 Participants
n=93 Participants
|
|
Age, Customized
36-45 Years
|
4 Participants
n=93 Participants
|
|
Age, Customized
>45 Years
|
2 Participants
n=93 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=93 Participants
|
|
Sex: Female, Male
Male
|
11 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
White
|
9 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
1 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Asian
|
2 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Hispanic or Latino
|
2 Participants
n=93 Participants
|
|
Race/Ethnicity, Customized
Not Hispanic or Latino
|
10 Participants
n=93 Participants
|
PRIMARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Maximum Plasma Concentration (Cmax) of Midazolam When Administered Alone and With PF-07321332/Ritonavir
|
9.812 ng/mL
Geometric Coefficient of Variation 38
|
36.18 ng/mL
Geometric Coefficient of Variation 17
|
—
|
PRIMARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
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
|
363.9 ng*hr/mL
Geometric Coefficient of Variation 13
|
—
|
PRIMARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
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
|
353.8 ng*hr/mL
Geometric Coefficient of Variation 13
|
—
|
SECONDARY outcome
Timeframe: Baseline up to Day 28Population: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=11 Participants
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 100 mg + Midazolam 2 mg
n=11 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Participants with adverse events (All Causalities)
|
4 Participants
|
9 Participants
|
7 Participants
|
|
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Participants with adverse events (Treatment related)
|
4 Participants
|
9 Participants
|
7 Participants
|
|
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Participants with severe adverse events
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Participants with serious adverse events
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: Baseline up to Day 28Population: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=11 Participants
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 100 mg + Midazolam 2 mg
n=11 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Number of Participants With Laboratory Abnormalities
HEMATOLOGY - Lymphocytes/Leukocytes (%) >1.2x ULN
|
0 Participants
|
0 Participants
|
1 Participants
|
|
Number of Participants With Laboratory Abnormalities
HEMATOLOGY - Neutrophils (10^3/mm^3) <0.8x LLN
|
0 Participants
|
0 Participants
|
1 Participants
|
|
Number of Participants With Laboratory Abnormalities
HEMATOLOGY - Neutrophils/Leukocytes (%) <0.8x LLN
|
0 Participants
|
1 Participants
|
1 Participants
|
|
Number of Participants With Laboratory Abnormalities
HEMATOLOGY - Eosinophils/Leukocytes (%) >1.2x ULN
|
0 Participants
|
1 Participants
|
1 Participants
|
|
Number of Participants With Laboratory Abnormalities
HEMATOLOGY - Monocytes/Leukocytes (%) >1.2x ULN
|
1 Participants
|
1 Participants
|
2 Participants
|
|
Number of Participants With Laboratory Abnormalities
HEMATOLOGY - Prothrombin Time (sec) >1.1x ULN
|
0 Participants
|
0 Participants
|
1 Participants
|
|
Number of Participants With Laboratory Abnormalities
CLINICAL CHEMISTRY - Thyrotropin (uIU/mL) <0.8x LLN
|
1 Participants
|
1 Participants
|
1 Participants
|
|
Number of Participants With Laboratory Abnormalities
CLINICAL CHEMISTRY - Fibrinogen (mg/dL) >1.25x Baseline
|
1 Participants
|
1 Participants
|
0 Participants
|
|
Number of Participants With Laboratory Abnormalities
URINALYSIS - URINE Hemoglobin (Scalar) ≥1
|
2 Participants
|
1 Participants
|
3 Participants
|
SECONDARY outcome
Timeframe: Baseline up to Day 28Population: 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.
Baseline was the last predose recording in each study period. Only post baseline values are included in this analysis
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=11 Participants
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 100 mg + Midazolam 2 mg
n=11 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Number of Participants With Vital Signs Abnormalities
|
0 Participants
|
1 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: Baseline up to Day 28Population: 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.
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
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=11 Participants
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 100 mg + Midazolam 2 mg
n=11 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
PR INTERVAL, AGGREGATE (MSEC) - Value≥300
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QRS DURATION, AGGREGATE (MSEC) - Value≥140
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QRS DURATION, AGGREGATE (MSEC) - %Change≥50%
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QTCF INTERVAL, AGGREGATE (MSEC) - 450<Value≤480
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QTCF INTERVAL, AGGREGATE (MSEC) - Value>500
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QTCF INTERVAL, AGGREGATE (MSEC) - 30<Change≤60
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QTCF INTERVAL, AGGREGATE (MSEC) - Change>60
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
PR INTERVAL, AGGREGATE (MSEC) - %Change≥25/50%
|
0 Participants
|
0 Participants
|
0 Participants
|
|
Number of Participants With Electrocardiogram (ECG) Abnormalities
QTCF INTERVAL, AGGREGATE (MSEC) - 480<Value≤500
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Cmax of Midazolam When Administered Alone and With Ritonavir
|
9.812 ng/mL
Geometric Coefficient of Variation 38
|
38.03 ng/mL
Geometric Coefficient of Variation 18
|
—
|
SECONDARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
AUCinf of Midazolam When Administered Alone and With Ritonavir
|
26.13 ng*hr/mL
Geometric Coefficient of Variation 45
|
418.6 ng*hr/mL
Geometric Coefficient of Variation 15
|
—
|
SECONDARY outcome
Timeframe: 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-dosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
AUClast of Midazolam When Administered Alone and With Ritonavir
|
25.02 ng*hr/mL
Geometric Coefficient of Variation 44
|
408.8 ng*hr/mL
Geometric Coefficient of Variation 15
|
—
|
SECONDARY outcome
Timeframe: 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 postdosePopulation: 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.
CL/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/AUCinf.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
n=10 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
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
|
5.500 Litre/hour
Geometric Coefficient of Variation 13
|
4.776 Litre/hour
Geometric Coefficient of Variation 15
|
SECONDARY outcome
Timeframe: 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 postdosePopulation: 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.
Vz/F for midazolam following single dose administration with and without PF-07321332/ritonavir or ritonavir was calculated by Dose/(AUCinf • kel).
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
n=10 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
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
|
79.84 Litre
Geometric Coefficient of Variation 28
|
76.43 Litre
Geometric Coefficient of Variation 31
|
SECONDARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
n=10 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Time for Cmax (Tmax) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir
|
1.00 Hour
Interval 0.5 to 1.1
|
1.00 Hour
Interval 0.5 to 1.05
|
1.02 Hour
Interval 0.5 to 3.17
|
SECONDARY outcome
Timeframe: 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 postdosePopulation: 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.
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.
Outcome measures
| Measure |
Midazolam 2 mg
n=10 Participants
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=10 Participants
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 100 mg + Midazolam 2 mg
n=10 Participants
Participants administer Ritonavir orally every 12 hours for a total of 9 doses on Day1-5 and Midazolam orally as a single dose on Day 5, followed by serial PK sampling and a 7-day washout (Duration: Day 1 to Day 12).
|
|---|---|---|---|
|
Terminal Half-life (t1/2) of Midazolam When Administered Alone, With PF-07321332/Ritonavir, and With Ritonavir
|
4.988 Hour
Standard Deviation 2.2058
|
10.47 Hour
Standard Deviation 2.9096
|
11.54 Hour
Standard Deviation 3.4741
|
Adverse Events
Midazolam 2 mg
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
Ritonavir 100 mg + Midazolam 2 mg
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Midazolam 2 mg
n=10 participants at risk
Midazolam administered as a single dose on Day 1
|
PF-07321332 300 mg/Ritonavir 100 mg + Midazolam 2 mg
n=11 participants at risk
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 100 mg + Midazolam 2 mg
n=11 participants at risk
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
|
|---|---|---|---|
|
Cardiac disorders
Nodal rhythm
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Gastrointestinal disorders
Abdominal discomfort
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Gastrointestinal disorders
Abdominal pain
|
0.00%
0/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Gastrointestinal disorders
Diarrhoea
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Gastrointestinal disorders
Dry mouth
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Gastrointestinal disorders
Dyspepsia
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Gastrointestinal disorders
Haematochezia
|
0.00%
0/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
General disorders
Chest discomfort
|
10.0%
1/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
General disorders
Fatigue
|
10.0%
1/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
General disorders
Vessel puncture site pain
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
General disorders
Vessel puncture site reaction
|
10.0%
1/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Infections and infestations
Folliculitis
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.00%
0/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Nervous system disorders
Dysgeusia
|
0.00%
0/10 • Baseline up to Day 28
|
54.5%
6/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Nervous system disorders
Headache
|
10.0%
1/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Nervous system disorders
Somnolence
|
10.0%
1/10 • Baseline up to Day 28
|
27.3%
3/11 • Baseline up to Day 28
|
27.3%
3/11 • Baseline up to Day 28
|
|
Psychiatric disorders
Nightmare
|
10.0%
1/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Reproductive system and breast disorders
Heavy menstrual bleeding
|
0.00%
0/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Reproductive system and breast disorders
Vaginal haemorrhage
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
10.0%
1/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Respiratory, thoracic and mediastinal disorders
Dry throat
|
10.0%
1/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
|
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
|
0.00%
0/10 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
|
Skin and subcutaneous tissue disorders
Rash maculo-papular
|
0.00%
0/10 • Baseline up to Day 28
|
0.00%
0/11 • Baseline up to Day 28
|
9.1%
1/11 • Baseline up to Day 28
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place