A Drug-Drug Interaction Study to Examine the Impact of Itraconazole and Cyclosporine on PF-07081532 Pharmacokinetics in Overweight or Obese Adults

Study Overview
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Brief Summary
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This is a Phase 1, open-label, fixed-sequence, 3-period study to evaluate the effect of multiple doses of itraconazole and a single dose of cyclosporine on the single-dose PK of PF-07081532 in otherwise healthy, overweight or obese, adult female and male participants. The 3 study periods will be conducted consecutively without a break.

Official Title
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A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO EVALUATE THE EFFECT OF ITRACONAZOLE AND CYCLOSPORINE ON THE SINGLE-DOSE PHARMACOKINETICS OF PF-07081532 IN OVERWEIGHT OR OBESE ADULT PARTICIPANTS

Conditions
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Healthy

Intervention / Treatment
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* Drug: PF-07081532
* Device: Cyclosporine
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Otherwise healthy female and male participants must be at least 18 years of age at the time of signing the ICD (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, physical examination, including blood pressure and pulse rate measurement, standard 12-lead ECG and clinical laboratory tests). BMI: ≥25.0 kg/m2 at Screening. Stable body weight, defined as <5 kg change (per participant report) for 90 days before Screening. Exclusion Criteria: 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). Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at Screening. Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin) Personal or family history of MTC or MEN2, or study participants with suspected MTC per the investigator's judgment. Acute pancreatitis, a history of repeated episodes of acute pancreatitis, or history of chronic pancreatitis. Symptomatic gallbladder disease. Medical history or characteristics suggestive of genetic or syndromic obesity or obesity induced by other endocrinological disorders (eg, Cushing Syndrome). History of depressive disorder or history of other severe psychiatric disorders (eg, schizophrenia or bipolar disorder) within the last 2 years from screening. Known medical history of active liver disease, including chronic hepatitis B or C, primary biliary cirrhosis, alcoholic liver disease, primary sclerosing cholangitis, autoimmune hepatitis, overlap syndrome, or prior known drug-induced liver injury. History of HIV infection. Any lifetime history of a suicide attempt. Use of prohibited medications Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that mayaffect participant safety or interpretation of study result. Participants with clinical laboratory test abnormalities at Screening. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Period 1: PF-07081532<br>Participants will receive PF-07081532 as a single dose on Day 1. | Drug: PF-07081532<br>* Oral Tablet<br>|
| Experimental: Period 2: Cyclosporine + PF-07081532<br>Participants will receive a single dose of PF-07081532 and a single dose of cyclosporine on Day 1. | Drug: PF-07081532<br>* Oral Tablet<br>Device: Cyclosporine<br>* Oral Solution<br>|
| Experimental: Period 3: Itraconazole + PF-07081532<br>Participants will receive itraconazole daily for 9 days plus a single dose of PF-07081532 on Day 4. | Drug: PF-07081532<br>* Oral Tablet<br>Drug: Itraconazole<br>* Oral Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCinf (if data permits otherwise AUClast): To estimate the effect of muliple dose itraconazole on thes single dose of PF-07081532 in otherwise healthy, overweight or obese participants. | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose | 
| AUCinf (if data permita otherwise AUClast): To estimate the effect of single dose of cyclosporine on the single dose of PF-07081532 in otherwise healthy, overweight or obese participants. | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants reporting Treatment Emergent Adverse Events (TEAE) |  | up to 28 days | 
| Percentage of participants reporting clinical laboraroy abnormalities | including vital signs, body weight, and ECG parameters. | up to 28 days | 
| Number of Participants responding yes to any suicidal behavior question according to Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Participants who respond yes to any suicidal behavioral question on the C-SSRS will not be permitted in the study | Day 1, Day 10 or Early Termination visit | 
| Number of participants with a score of ≥15 on Patient Health Questionnaire-9 (PHQ-9) | PHQ9-9 is a 9 item self-report scale for the assessment of depressive symptoms. A PHQ-9 score of ≥15 indicates clinically significant depression and serves as an exclusion criterion for this study | Day 1, Day 10 or Early Termination visit | 
| Maximum Observed Plasma Concentration (Cmax) of PF-07081532 |  | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07081532 |  | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose | 
| Apparent Oral Clearance (CL/F) of PF-07081532 |  | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose | 
| Apparent Volume of Distribution (Vz/F) of PF-07081532 |  | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose | 
| Plasma Decay Half-Life (t1/2 of PF-07081532 |  | 0 (pre-dose) 0.5 1 2 4 6 8 10 12 14 24 36 48 72 96 and 120 hours post dose |