Two different groups of healthy volunteers will be chronically treated with GLP-1 drugs PF-07081532 or alternatively Semaglutide. The effect of these GLP-1 drugs on a single dose of the common sedative medication midazolam blood levels will be measured. The effect of chronic PF-07081532 on single doses of the common stomach acid medication omeprazole, and common birth control medication blood levels will also be measured. The hypothesis is that chronic administration of the GLP-1 drugs will minimally affect blood levels from these common medications.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
32
Experimental oral GLP-1 drug
Approved and marketed GLP-1 drug for subcutaneous injection.
Anaheim Clinical Trials, LLC
Anaheim, California, United States
Cohort 1: Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Midazolam in Periods 1, 4 and 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Area Under the Plasma Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Omeprazole in Periods 1, 4 and 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole PK at the preset time points described in the Time Frame. AUClast calculated area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: AUClast of Levonorgestrel (LE) in Periods 2, 5,and 8
LE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for LE PK at the preset time points described in the Time Frame. AUClast calculated area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to LE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: AUCinf of Ethinyl Estradiol (EE) in Periods 2, 5,and 8
EE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for EE PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to EE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 2: AUCinf of Midazolam in Period 1 and 3
Midazolam was given on Day 1 in Period 1 and 3 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Number of Participants With All-Causality and Treatment-Related TEAEs
An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness to study treatment was assessed by the investigator. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events were events between first dose of study treatment and up to approximately 35 days that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From first dose (Day 1) to follow-up telephone contact (Days 153 to 160) in Cohort 1
Cohort 1: Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)
Laboratory tests (including hematology, clinical chemistry, urinalysis) were reported and abnormalities were defined for laboratory values that met specific criteria.
Time frame: From first dose (Day 1) to follow-up telephone contact (Days 153 to 160) in Cohort 1
Cohort 1: Percentage of Change From Baseline in Body Weight by Period 9 Day 1
Percentage of changes from Baseline in body weight of the participants were measured.
Time frame: From baseline (last pre-dose measurement in Period 1) to Period 9 Day 1 (Day 124)
Cohort 1: Number of Participants With Completed Suicide, Suicide Attempt, Preparatory Acts Towards Imminent Suicidal Behavior, Suicidal Ideation, or Self-Injurious Behavior of No Suicidal Intent As Assessed on the C-SSRS
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS items were mapped to the following categories: completed suicide, suicide attempt, preparatory acts towards imminent suicidal behavior, suicidal ideation, and self-injurious behavior of no suicidal intent. Number of participants with completed suicide, suicide attempt, preparatory acts towards imminent suicidal behavior, suicidal ideation, or self-injurious behavior of no suicidal intent as assessed on the C-SSRS are reported below.
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Time frame: Screening, Study Day -1 (D-1) (ie, Period 1 Day -1 [P1D-1]), D7 (P3D1), D21 (P3D15), D35 (P4D1), D54 (P6D14), D68 (P6D28), D82 (P6D42), D96 (P6D56), D103 (P6D63), D110 (P8D6) and at follow up visit D132-135
Cohort 1: Patient Health Quessionare-9 (PHQ-9) Total Scores
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The PHQ-9 is completed by participants and reviewed by site staff at the pre-defined time points. The total score is derived by adding the corresponding values of responses to each item. The total score ranges from 0 to 27, with the following interpretation: 1-4: Minimal depression; 5-9: Mild depression; 10-14: Moderate depression; 15-19: Moderately severe depression; 20-27: Severe depression.
Time frame: Screening, Study Day -1 (D-1) (ie, Period 1 Day -1 [P1D-1]), D7 (P3D1), D21 (P3D15), D35 (P4D1), D54 (P6D14), D68 (P6D28), D82 (P6D42), D96 (P6D56), D103 (P6D63), D110 (P8D6) and at follow up visit D132-135
Cohort 1: AUCinf of Midazolam in Period 9
Midazolam was given on Day 1 in Period 9 of Cohort 1 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time frame: For Cohort 1 Period 9: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1
Cohort 1: Maximum Observed Concentration (Cmax) of Midazolam in Period 1, 4, 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Time for Cmax (Tmax) of Midazolam in Period 1, 4, 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. Tmax was defined as time for Cmax and was observed directly from data.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Apparent Clearance (CL/F) of Midazolam in Period 1, 4, 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. CL/F was defined as apparent clearance and was calculated as dose/AUCinf.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Apparent Volume of Distribution (Vz/F) of Midazolam in Period 1, 4, 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. Vz/F was defined as apparent volume of distribution and was calculated as dose/(AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Terminal Half-Life (t1/2) of Midazolam in Period 1, 4, 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. t1/2 was defined as terminal half life and was calculated as loge(2)/kel.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Cmax of Omeprazole in Period 1, 4, 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Tmax of Omeprazole in Period 1, 4, 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole PK at the preset time points described in the Time Frame. Tmax was defined as time for Cmax and was observed directly from data.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: CL/F of Omeprazole in Period 1, 4, 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole PK at the preset time points described in the Time Frame. CL/F was defined as apparent clearance and was calculated as dose/AUCinf.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Vz/F of Omeprazole in Period 1, 4, 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole PK at the preset time points described in the Time Frame. Vz/F was defined as apparent volume of distribution and was calculated as dose/(AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: t1/2 of Omeprazole in Period 1, 4, 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole PK at the preset time points described in the Time Frame. Vz/F was defined as apparent volume of distribution and was calculated as dose/(AUCinf ×kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Cmax of LE in Period 2, 5, 8
LE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for LE PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to LE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: Tmax of LE in Period 2, 5, 8
LE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for LE PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to LE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: CL/F of LE in Period 2, 5, 8
LE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for LE PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to LE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: Vz/F of LE in Period 2, 5, 8
LE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for LE PK at the preset time points described in the Time Frame. Vz/F was defined as apparent volume of distribution and was calculated as dose/(AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to LE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: t1/2 of LE in Period 2, 5, 8
LE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for LE PK at the preset time points described in the Time Frame. t1/2 was defined as terminal half life and was calculated as loge(2)/kel.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to LE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: Cmax of EE in Period 2, 5, 8
EE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for EE PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to EE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: Tmax of EE in Period 2, 5, 8
EE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for EE PK at the preset time points described in the Time Frame. Tmax was defined as time for Cmax and was observed directly from data.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to EE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: CL/F of EE in Period 2, 5, 8
EE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for EE PK at the preset time points described in the Time Frame. CL/F was defined as apparent clearance and was calculated as dose/AUCinf.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to EE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: Vz/F of EE in Period 2, 5, 8
EE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for EE PK at the preset time points described in the Time Frame. Vz/F was defined as apparent volume of distribution and was calculated as dose/(AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to EE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: t1/2 of EE in Period 2, 5, 8
EE was given on Day 1 in Period 2, 5, 8 of Cohort 1 and blood samples were collected for EE PK at the preset time points described in the Time Frame. t1/2 was defined as terminal half life and was calculated as loge(2)/kel.
Time frame: For Cohort 1 Periods 2, 5, and 8: At 0 (prior to EE dose), 0.75, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours post LE dose on Day 1 of each period
Cohort 1: Metabolite/Parent Ratio for AUCinf (MRAUCinf) of 1-Hydroxy Midazolam in Period 1, 4, 7
Midazolam was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for midazolam (parent) and and its metabolite 1-Hydroxy Midazolam PK at the preset time points described in the Time Frame. MRAUCinf was calculated as (AUCinf, metabolite/AUCinf, parent) \* (MWparent/MWmetabolite). MW = molecular weight.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: MRAUCinf of 5-Hydroxy Omeprazole in Period 1, 4, 7
Omeprazole was given on Day 1 in Period 1, 4, 7 of Cohort 1 and blood samples were collected for omeprazole (parent) and and its metabolite 5-Hydroxy omeprazole PK at the preset time points described in the Time Frame. MRAUCinf was calculated as (AUCinf, metabolite/AUCinf, parent) \* (MWparent/MWmetabolite). MW = molecular weight.
Time frame: For Cohort 1 Periods 1, 4, and 7: At 0 (prior to omeprazole dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 1: Area Under the Plasma Concentration-Time Profile From Time 0 to 24 Hours (AUC24) of PF-07081532 in Period 3 and 6
PF-07081532 was given titrated to 80 mg QD on Day 1-28 of Period 3, and titrated to 260 mg QD on Day 1-63 of Period 6 in Cohort 1, and blood samples were collected for PF-07081532 PK at the preset time points described in the Time Frame. AUC24 was defined as area under the plasma concentration-time profile from time 0 to 24 hours and was determined using the linear/log trapezoidal method.
Time frame: For Cohort 1 Periods 3 and 6: At 0 , 0.5, 1, 2, 4, 6, 8, 10, 14, and 24 hours post PF-07081532 dose on Day 28 of Period 3 and Day 63 of Period 6
Cohort 1: Cmax of PF-07081532 in Period 3 and 6
PF-07081532 was given titrated to 80 mg QD on Day 1-28 of Period 3, and titrated to 260 mg QD on Day 1-63 of Period 6 in Cohort 1, and blood samples were collected for PF-07081532 PK at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 1 Periods 3 and 6: At 0 , 0.5, 1, 2, 4, 6, 8, 10, 14, and 24 hours post PF-07081532 dose on Day 28 of Period 3 and Day 63 of Period 6
Cohort 1: Tmax of PF-07081532 in Period 3 and 6
PF-07081532 was given titrated to 80 mg QD on Day 1-28 of Period 3, and titrated to 260 mg QD on Day 1-63 of Period 6 in Cohort 1, and blood samples were collected for PF-07081532 PK at the preset time points described in the Time Frame. Tmax was defined as time for Cmax and was observed directly from data.
Time frame: For Cohort 1 Periods 3 and 6: At 0 , 0.5, 1, 2, 4, 6, 8, 10, 14, and 24 hours post PF-07081532 dose on Day 28 of Period 3 and Day 63 of Period 6
Cohort 2: Number of Participants With All-Causality and Treatment-Related TEAEs
An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness to study treatment was assessed by the investigator. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events were events between first dose of study treatment and up to approximately 35 days that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From first dose (Day 1) to follow-up telephone contact (Days 193 to 200) in Cohort 2
Cohort 2: Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)
Laboratory tests (including hematology, clinical chemistry, urinalysis) were reported and abnormalities were defined for laboratory values that met specific criteria.
Time frame: From first dose (Day 1) to follow-up telephone contact (Days 193 to 200) in Cohort 2
Cohort 2: Percentage of Change From Baseline in Body Weight by Period 4 Day 1
Percentage of changes from Baseline in body weight of the participants were measured.
Time frame: From baseline (last pre-dose measurement in Period 1) to Period 4 Day 1 (Day 165)
Cohort 2: Number of Participants With Completed Suicide, Suicide Attempt, Preparatory Acts Towards Imminent Suicidal Behavior, Suicidal Ideation, or Self-Injurious Behavior of No Suicidal Intent As Assessed on the C-SSRS
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS items were mapped to the following categories: completed suicide, suicide attempt, preparatory acts towards imminent suicidal behavior, suicidal ideation, and self-injurious behavior of no suicidal intent. Number of participants with completed suicide, suicide attempt, preparatory acts towards imminent suicidal behavior, suicidal ideation, or self-injurious behavior of no suicidal intent as assessed on the C-SSRS are reported below.
Time frame: Screening, D-1 (P1D-1), P2 Week 5 [W5], P2W9, P2W13, P2W17, D150 (P3D2), at follow up visit (Day 172-175)
Cohort 2: PHQ-9 Total Scores
The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The PHQ-9 is completed by participants and reviewed by site staff at the pre-defined time points. The total score is derived by adding the corresponding values of responses to each item. The total score ranges from 0 to 27, with the following interpretation: 1-4: Minimal depression; 5-9: Mild depression; 10-14: Moderate depression; 15-19: Moderately severe depression; 20-27: Severe depression.
Time frame: Screening, D-1 (P1D-1), P2 Week 5 [W5], P2W9, P2W13, P2W17, D150 (P3D2), at follow up visit (Day 172-175)
Cohort 2: AUCinf of Midazolam in Period 4
Midazolam was given on Day 1 in Period 4 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time frame: For Cohort 2 Period 4: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14 and 24 hours post midazolam dose on Day 1
Cohort 2: Cmax of Midazolam in Period 1 and 3
Midazolam was given on Day 1 in Period 1 and 3 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. Cmax was defined as maximum observed concentration and was observed directly from data.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 2: Tmax of Midazolam in Period 1 and 3
Midazolam was given on Day 1 in Period 1 and 3 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. Tmax was defined as time for Cmax and was observed directly from data.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 2: CL/F of Midazolam in Period 1 and 3
Midazolam was given on Day 1 in Period 1 and 3 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. CL/F was defined as apparent clearance and was calculated as dose/AUCinf.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 2: Vz/F of Midazolam in Period 1 and 3
Midazolam was given on Day 1 in Period 1 and 3 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. Vz/F was defined as apparent volume of distribution and was calculated as dose/(AUCinf\*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration time curve.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 2: t1/2 of Midazolam in Period 1 and 3
Midazolam was given on Day 1 in Period 1 and 3 of Cohort 2 and blood samples were collected for midazolam pharmacokinetic (PK) at the preset time points described in the Time Frame. t1/2 was defined as terminal half life and was calculated as loge(2)/kel.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period
Cohort 2: MRAUCinf of 1-Hydroxy Midazolam in Period 1, 3, 4
Midazolam was given on Day 1 in Period 1, 3, 4 of Cohort 2 and blood samples were collected for midazolam (parent) and and its metabolite 1-Hydroxy Midazolam PK at the preset time points described in the Time Frame. MRAUCinf was calculated as (AUCinf, metabolite/AUCinf, parent) \* (MWparent/MWmetabolite). MW = molecular weight.
Time frame: For Cohort 2 Periods 1 and 3: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24 hours post midazolam dose on Day 1 of each period