A Study to Evaluate the Effect of the Experimental GLP-1 Drug PF-07081532 on Blood Levels of Common Birth Control Pills, and Drugs Omeprazole and Midazolam, and Effect of GLP-1 Drug Semaglutide on Midazolam Blood Levels in Healthy Adults With Weight in the Obesity Range

Study Overview
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Brief Summary
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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.

Official Title
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A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO EVALUATE THE EFFECT OF TWO STEADY-STATE DOSE LEVELS OF PF-07081532 ON THE PHARMACOKINETICS OF SINGLE-DOSE MIDAZOLAM, OMEPRAZOLE AND AN ORAL CONTRACEPTIVE, AND THE EFFECT OF STEADY-STATE SEMAGLUTIDE ON THE PHARMACOKINETICS OF SINGLE-DOSE MIDAZOLAM, IN OBESE ADULT FEMALE PARTICIPANTS

Conditions
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Obesity

Intervention / Treatment
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* Drug: PF-07081532
* Drug: Semaglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy (no clinically relevant abnormalities) BMI 30.0-45.4 inclusive Exclusion Criteria: Current or history of significant clinical condition Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 or 14 days or 5 half-lives (whichever is longer) Pregnant Breast feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The overall design is randomized, open-label, fixed-sequence. Cohort 1 will consist of 9 periods while Cohort 2 will consist of 4 periods.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: PF-07081532<br>Cohort 1 is an open-label, 9 period, fixed-sequence design to evaluate the effect of 2 steady state dose levels of PF-07081532 on the SD pharmacokinetics of midazolam and omeprazole, administered simultaneously, and an OC (LE/EE) in otherwise healthy obese adult female participants with a BMI ≥30 kg/m2. | Drug: PF-07081532<br>* Experimental oral GLP-1 drug<br>|
| Experimental: Cohort 2: Semaglutide<br>Cohort 2 is an open label, 4-period, fixed-sequence design to evaluate the effect of steady state semaglutide on the SD PK of midazolam in obese adult female participants with a BMI ≥30 kg/m2 | Drug: Semaglutide<br>* Approved and marketed GLP-1 drug for subcutaneous injection.<br>* Other names: Wegovy, Ozempic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for midazolam and omeprazole. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for midazolam and omeprazole. | Will be calculated if data do not permit calculation of AUCinf. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Area Under the Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for levonorgestrel and ethinyl estradiol. | Will be calculated as permitted by the data | 0, 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1. | 
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for levonorgestrel and ethinyl estradiol. | Will be calculated if data do not permit calculation of AUCinf. | , 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1 | 
| Area Under the Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for midazolam. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2. | 
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for midazolam. | Will be calculated if data do not permit calculation of AUCinf. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Treatment-Emergent Adverse Events |  | Baseline through End of Study (Day 160 Cohort 1 and Day 200 Cohort 2) | 
| Number of Participants with Clinical Laboratory Abnormalities |  | Baseline through the In-patient Follow-up Visit (Day 135 Cohort 1 and Day 175 Cohort 2) | 
| Change in Body Weight |  | Baseline through the In-patient Follow-up Visit (Day 135 Cohort 1 and Day 175 Cohort 2) | 
| Assessment of mental health as determined by Columbia Suicide Severity Rating Scale (C-SSRS) |  | Baseline through the In-patient Follow-up Visit (Day 135 Cohort 1 and Day 175 Cohort 2) | 
| Assessment of mental health as determined by Patient Health Questionnaire-9P (HQ 9) |  | Baseline through the In-patient Follow-up Visit (Day 135 Cohort 1 and Day 175 Cohort 2) | 
| Area Under the Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for midazolam | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Period 9 for Cohort 1. | 
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for midazolam. | Will be calculated if data do not permit calculation of AUCinf. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Period 9 for Cohort 1 | 
| Area Under the Curve From Time Zero Extrapolated to Infinite Time (AUCinf) for midazolam. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Period 4 for Cohort 2 | 
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for midazolam. | Will be calculated if data do not permit calculation of AUCinf. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Period 4 for Cohort 2. | 
| Maximum observed plasma concentration (Cmax) for midazolam and omeprazole. |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for midazolam and omeprazole. |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1 | 
| Apparent Oral Clearance (CL/F) for midazolam and omeprazole. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Apparent Volume of Distribution (Vz/F) for midazolam and omeprazole. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Plasma Elimination Half-Life (t1/2) for midazolam and omeprazole. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Maximum observed plasma concentration (Cmax) for levonorgestrel and ethinyl estradiol. |  | 0, 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for levonorgestrel and ethinyl estradiol. |  | 0, 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1. | 
| Apparent Oral Clearance (CL/F) for levonorgestrel and ethinyl estradiol | Will be calculated as permitted by the data. | 0, 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1. | 
| Apparent Volume of Distribution (Vz/F) for levonorgestrel and ethinyl estradiol. | Will be calculated as permitted by the data. | 0, 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1. | 
| Plasma Elimination Half-Life (t1/2) for levonorgestrel and ethinyl estradiol. | Will be calculated as permitted by the data. | 0, 0.75, 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post dose in Periods 2, 5, and 8 for Cohort 1. | 
| Metabolite/parent ratio for midazolam (MRAUCinf [1-hydroxymidazolam AUCinf/midazolam AUCinf]) |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Metabolite/parent ratio for omeprazole (MRAUCinf [5-hydroxyomeprazole AUCinf/omeprazole AUCinf]) |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1, 4, and 7 for Cohort 1. | 
| Metabolite/parent ratio for midazolam (MRAUCinf [1-hydroxymidazolam AUCinf/midazolam AUCinf]) |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2. | 
| Area under the plasma concentration-time profile from time zero to time 24 hours (AUC24) for PF-07081532. |  | 0, 0.5, 1, 2, 4, 6, 8, 10, 14, and 24 hours post dose in Period 3 Day 28 and Period 6 Day 63. | 
| Maximum observed plasma concentration (Cmax) for PF-07081532 |  | 0, 0.5, 1, 2, 4, 6, 8, 10, 14, and 24 hours post dose in Period 3 Day 28 and Period 6 Day 63. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-07081532. |  | 0, 0.5, 1, 2, 4, 6, 8, 10, 14, and 24 hours post dose in Period 3 Day 28 and Period 6 Day 63. | 
| Maximum observed plasma concentration (Cmax) for midazolam. |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for midazolam. |  | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2. | 
| Apparent Oral Clearance (CL/F) for midazolam. | Will be calculated as permitted by the data. | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2. | 
| Plasma Elimination Half-Life (t1/2) for midazolam. | Will be calculated as permitted by the data | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post dose in Periods 1 and 3 for Cohort 2. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Midazolam, Omeprazole, PF-07081532