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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Itraconazole; Drug: PF-07081532; Device: Cyclosporine

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • New Haven Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. 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).
2. BMI: ≥25.0 kg/m2 at Screening.
3. Stable body weight, defined as <5 kg change (per participant report) for 90 days before Screening.

Exclusion Criteria:

1. 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).
2. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at Screening.
3. Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin)
4. Personal or family history of MTC or MEN2, or study participants with suspected MTC per the investigator's judgment.
5. Acute pancreatitis, a history of repeated episodes of acute pancreatitis, or history of chronic pancreatitis.
6. Symptomatic gallbladder disease.
7. Medical history or characteristics suggestive of genetic or syndromic obesity or obesity induced by other endocrinological disorders (eg, Cushing Syndrome).
8. History of depressive disorder or history of other severe psychiatric disorders (eg, schizophrenia or bipolar disorder) within the last 2 years from screening.
9. 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.
10. History of HIV infection.
11. Any lifetime history of a suicide attempt.
12. Use of prohibited medications
13. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest.
14. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that mayaffect participant safety or interpretation of study result.
15. Participants with clinical laboratory test abnormalities at Screening. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine	AUCinf is area under the plasma concentration-time profile from time zero extrapolated to infinite time. AUCinf is caluculated by AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis.	Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Any AEs occurring following start of treatment were considered as treatment emergent adverse event (TEAE). Events that occur during follow-up within the lag time of up to 35 days after the last dose of study intervention were counted as treatment emergent and attributed to the last treatment taken.	From the first dose up to 35 days after administration of the final dose of study intervention (Period 3 Day 9, Study Day 19), the maximum duration was 54 Days
Number of Participants With Laboratory Abnormalities	Participants with laboratory abnormalities (without regard to baseline abnormality) that met pre-specified criteria: For HEMATOLOGY, 1) Erythrocyte (Ery.) Mean Corpuscular Volume (fL) < 0.9*Lower limit of normal (LLN), 2) Ery. Mean Corpuscular Hemoglobin (picograms [pg]/cell) < 0.9*LLN; 3） Eosinophils/Leukocytes (%)> 1.2*upper limit of normal (ULN); for CLINICAL CHEMISTRY, Urate (mg/dL)> 1.2*ULN; for URINALYSIS, Urine Hemoglobin (Scalar)≥ 1.	Baseline (pre-dose on Day 1), Period 2 Day 5 (Study Day 10), and Period 3 Day 10 (Study Day 20)
Number of Participants Meeting Pre-Specified Criteria of Vital Signs	Pre-specified criteria of vital signs included: Supine diastolic blood pressure (BP) <50mmHg, change from baseline maximum (max) decrease or increase >=20mmHg; supine pulse rate min< 40 beats per minute (bpm), max> 120 bpm; Supine systolic BP: Value <90 mmHg, change from baseline max decrease or increase >=30mmHg	Pre-dose Day 1 in periods 1, 2 and 3 (Study Days 1, 6, and 11, respectively), and prior to discharge on Period 3 Day 10 (Study Day 20)
Change From Baseline in Body Weight at the End of Periods 1, 2, and 3	Observed value at baseline and change from baseline in body weight at Day 5 of Period 1 , Day 5 of Period 2, and Day 10 of Period 3 were summarized.	Baseline (pre-dose on Day 1), Day 5 of Period 1 (Study Day 5), Day 5 of Period 2 (Study Day 10), and Day 10 of Period 3 (Study Day 20)
Number of Participants Meeting Pre-Specified Criteria of Electrocardiogram (ECGs)	The pre-specified criteria of ECG included: QT interval, aggregated: value >500 millisecond (msec); corrected QT Fridericia method (QTCF) interval, aggregated: 450<=value<480 msec, 480<=value<500 msec, value>=500 msec, 30<=changes<60msec, and changes>=60msec.	Pre-dose Day 1 in periods 1, 2 and 3 (Study Days 1, 6, and 11, respectively), and prior to discharge on Period 3 Day 10 (Study Day 20)
Number of Participants With Suicidal Ideation or Behavior 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 question related to suicidal ideation or behavioral are reported in this outcome measure.	Period 1 Day -1 (Study Day -1), Period 3 Day 10 (Study Day 20) 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 was reported in this outcome measure. The total score ranges from 0 to 27 with the following interpretation: Score 1-4: minimal depression; Score 5-9: Mild depression; Score 10-14: moderate depression; Score 15-19 moderately severe depression; Score 20-27: Severe depression	Period 1 Day -1 (Study Day -1), Period 3 Day 10 (Study Day 20) or Early Termination visit
Maximum Observed Plasma Concentration (Cmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine	Cmax is the maximum observed concentration and is observed directly from data.	Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Time to Cmax (Tmax) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine	Tmax is the Time to Cmax and is observed directly from data as time of first occurrence.	Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Apparent Oral Clearance (CL/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine	CL/F is the apparent oral clearance and is calculated by Dose/AUCinf.	Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Apparent Oral Volume of Distribution (Vz/F) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine	Vz/F is the apparent volume of distribution and is calculated by Dose/ (AUCinf*kel), where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve	Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.
Terminal Half-life (t1/2) of Lotiglipron When Administered Alone and With Itraconazole or Cyclosporine	T1/2 is calculated by Loge(2)/kel, where kel is 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 decline were used in the regression.	Pre-dose of lotiglipron and at 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, and 144 (for Period 3 only) hours post dose of lotiglipron on Day 1 of Periods 1 and 2 and on Day 4 of Period 3.

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2023
• Primary Completion (Actual): May 29, 2023
• Study Completion (Actual): May 29, 2023

Study Registration Dates

• First Submitted: February 16, 2023
• First Submitted That Met QC Criteria: February 16, 2023
• First Posted (Actual): February 27, 2023

Study Record Updates

• Last Update Posted (Actual): September 23, 2024
• Last Update Submitted That Met QC Criteria: May 21, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Body Weight; Overweight; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Dermatologic Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Calcineurin Inhibitors; Itraconazole; Cyclosporine; Cyclosporins
• Other Study ID Numbers: C3991041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No