A Drug-Drug Interaction Study to Estimate the Effect of PF-07081532 on the Pharmacokinetics of Dabigatran and Rosuvastatin in Overweight or Obese Adult Participants

A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE STUDY TO ESTIMATE THE EFFECT OF PF-07081532 ADMINISTRATION ON THE SINGLE-DOSE PHARMACOKINETICS OF DABIGATRAN AND ROSUVASTATIN IN OVERWEIGHT OR OBESE ADULT PARTICIPANTS

The purpose of the study was to understand the effect of PF-07081532 on the movement of Dabigatran and Rosuvastatin into, though, and out of the body in healthy overweight or obese adult participants. This study also aims to collect data on safety and how tolerable the study medicine is.

The study is seeking for participants who are:

• Male or female who are 18 years of age or older.
• Healthy but are overweight or obese. Participants will receive dabigatran and rosuvastatin as single doses by mouth 3 times during the study. The amount of the study medicine PF-07081532 will be adjusted over time until any interactions are seen.

PF-07081532 is taken daily by mouth in 8 Study Periods while admitted into the study clinic over 53 days. Once discharged from the study clinic, participants will have a follow-up visit 7 to 10 days post last dose of study medicine. Then another follow-up via telephone contact, 28 to 35 days post last dose of study medicine.

Study Overview

• Status: Terminated
• Conditions: Healthy
• Intervention / Treatment: Drug: Dabigatran etexilate (DE); Drug: Rosuvastatin; Drug: PF-07081532

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

Contacts and Locations

Study Locations

• United States
  • Florida
    • South Miami, Florida, United States, 33143
      • Qps-Mra, Llc

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
2. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at Screening
3. History of myocardial infarction, unstable angina, arterial revascularization, mechanical prosthetic heart valve, stroke, New York Association Functional Class II-IV heart failure, or transient ischemic attack within 6 months of Screening
4. Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin)
5. Personal or family history of MTC or MEN2, or study participants with suspected MTC per the investigator's judgment
6. Acute pancreatitis, a history of repeated episodes of acute pancreatitis, or history of chronic pancreatitis
7. Symptomatic gallbladder disease
8. Medical history or characteristics suggestive of genetic or syndromic obesity or obesity induced by other endocrinological disorders
9. History of depressive disorder or history of other severe psychiatric disorders within the last 2 years from Screening
10. Any lifetime history of a suicide attempt
11. Known medical history of active liver disease, or prior known drug-induced liver injury
12. History of HIV infection
13. Recent history of bleeding, or risks of bleeding, or abnormal coagulation test (INR >1.3) result at Screening
14. Use of prohibited medications
15. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest
16. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study result
17. Participants with clinical laboratory test abnormalities at Screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Period 1; Participants will receive dabagatrin etexilate (DE) as a single dose	Drug: Dabigatran etexilate (DE); Dabigatran etexilate (DE) as oral capsule; Other Names: Pradaxa
Active Comparator: Period 2; Participants will receive rosuvastatin as a single dose	Drug: Rosuvastatin; Rosuvastatin as oral tablet; Other Names: Crestor
Active Comparator: Period 3; Participants will receive PF-07081532 daily titrated	Drug: PF-07081532; PF-07081532 as oral tablets; Other Names: Lotiglipron
Experimental: Period 4; Participants will receive PF-07081532 daily and DE as a single dose	Drug: Dabigatran etexilate (DE); Dabigatran etexilate (DE) as oral capsule; Other Names: Pradaxa; Drug: PF-07081532; PF-07081532 as oral tablets; Other Names: Lotiglipron
Experimental: Period 5; Participants will receive PF-07081532 daily and rosuvastatin as a single dose	Drug: Rosuvastatin; Rosuvastatin as oral tablet; Other Names: Crestor; Drug: PF-07081532; PF-07081532 as oral tablets; Other Names: Lotiglipron
Active Comparator: Period 6; Participants will receive PF-07081532 daily titrated	Drug: PF-07081532; PF-07081532 as oral tablets; Other Names: Lotiglipron
Experimental: Period 7; Participants will receive PF-07081532 daily and DE as a single dose	Drug: Dabigatran etexilate (DE); Dabigatran etexilate (DE) as oral capsule; Other Names: Pradaxa; Drug: PF-07081532; PF-07081532 as oral tablets; Other Names: Lotiglipron
Experimental: Period 8; Participants will receive PF-07081532 daily and rosuvastatin as a single dose	Drug: Rosuvastatin; Rosuvastatin as oral tablet; Other Names: Crestor; Drug: PF-07081532; PF-07081532 as oral tablets; Other Names: Lotiglipron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-Time Curve From Time Zero (0) Extrapolated to Infinity (AUCinf) of Total Dabigatran in Period 1, 4 and 7	AUCinf was calculated as AUClast + (Clast/kel), where AUClast is area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast), Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel is first-order elimination rate constant.	Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
Area Under the Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUClast) of Total Dabigatran in Period 1, 4 and 7	AUClast was determined using the linear/log trapezoidal method.	Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
AUCinf of Rosuvastatin in Period 2, 5 and 8	AUCinf was calculated as AUClast + (Clast/kel), where AUClast is area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast), Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel is first-order elimination rate constant.	Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8
AUClast of Rosuvastatin in Period 2, 5 and 8	AUClast was determined using the linear/log trapezoidal method.	Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)- All Causalities	An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were any untoward medical incidence in a participant during administered study intervention, whether or not these events are related to study intervention. AEs included both serious adverse events (SAEs) and all non-SAEs. An SAE was any untoward medical occurrence at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity and lastly causes a congenital anomaly/birth defect.	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)	The following laboratory parameters were assessed according to pre-specified criteria for abnormalities: a) hematology; erythrocytes mean corpuscular hemoglobin (picograms per cells ([pg/cells]) (less than[<]0.9*lower limit of normal [LLN]), eosinophils (10^9/Liter [L]), (more than[>]1.2*upper limit of normal [ULN]), prothrombin time (seconds)(>1.1*ULN), prothrombin international normalized ratio(>1.1*ULN); b) clinical chemistry; direct bilirubin(milligram per deciliter [mg/dL])(>1.5*ULN), aspartate aminotransferase(units per litre [U/L]) (>3.0*ULN), alanine aminotransferase(U/L)(> 3.0*ULN), gamma glutamyl transferase(U/L)(> 3.0*ULN), urate (mg/dL)(> 1.2*ULN), high density lipoprotein(HDL) cholesterol (mg/dl)(<0.8*LLN) and lipase(U/L)(> 1.5*ULN). Number of participants with any laboratory abnormalities (without regard to baseline abnormality) meeting pre-specified criteria are reported in this outcome measure.	During treatment of the study (maximum up to 48 days)
Number of Participants With Clinically Significant Vital Signs	Vital signs measurement included blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP] and pulse rate (PR) and were measured in a supine position after approximately 5 minutes of rest for the participant. Clinical significance in vital signs was judged by investigator.	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)
Percent Change From Baseline in Body Weight		Baseline, Day 1 and 8 of Period 3, Day 1 of Period 5, Day 5 and 12 of Period 6, Day 1 and 5 of Period 8 and follow-up (28-35 days post last dose; up to 76 to 83 days)
Number of Participants With Pre-defined Criteria of Electrocardiogram (ECG) Parameters	Pre-defined criteria for ECG abnormalities included: PR interval aggregate (millisecond [msec], max. >=300; baseline > 200 and max. increase >= 25 percent (%); baseline > 200 and max. increase >= 25%), QRS interval (msec, max >=140; max. increase >= 50%), QT interval correct by Frederica formula (QTCF) interval aggregate (msec, 450 < max <= 480; 480 < max. <= 500; max. > 500; 30 < max. increase <= 60; max. increase > 60). Number of participants with at least 1 ECG abnormality are reported in this outcome measure.	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)
Number of Participants 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. Yes/No responses are mapped to Columbia classification algorithm of suicide assessment (C-CASA) categories: completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. n this outcome measure, number of participants with positive response (response of "yes") for each of the five categories are reported.	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)
Number of Participants According to Patient Health Questionnaire-9 (PHQ-9) Classification	The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The questions included "little interest/pleasure in things", "feeling down depressed or hopeless", "trouble falling or staying asleep", "feeling tired or little energy", "poor appetite or overeating", "feeling bad about yourself", "trouble concentrating on things", "moving slowly or fidgety/restless" and "thoughts you be better off dead". Each item was scored on scale of "not at all" (0), "several days" (1), "more than half the days" (2) to "nearly every day" (3). Total score was obtained by addition of scores for each item and resulted into overall possible score range of 0-27. Higher score = greater severity.	Day 1 prior to treatment (Day -1) in Period 1; Day 8 of Period 3; Days 5 of Period 6; Day 1 and 5 of Period 8; Follow-up: up to 53 to 56 days post last dose of study intervention
Maximum Observed Concentration (Cmax) of Total Dabigatran in Period 1, 4 and 7		Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
Time for Cmax (Tmax) of Total Dabigatran in Period 1, 4 and 7		Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
Terminal Half-Life (t1/2) of Total Dabigatran in Period 1, 4 and 7	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
Apparent Volume of Distribution (Vz/F) of Total Dabigatran in Period 1, 4 and 7	Vz/F was calculated as dose/(AUCinf*kel). AUCinf was calculated as AUClast + (Clast/kel), where AUClast is area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast), Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel is first-order elimination rate constant.	Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
Apparent Oral Clearance (CL/F) of Total Dabigatran in Period 1, 4 and 7	CL/F was calculated as dose/AUCinf. AUCinf was calculated as AUClast + (Clast/kel), where AUClast is area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast), Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel is first-order elimination rate constant.	Pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours post dose of DE on Day 1 of Period 1, 4 and 7
Cmax of Rosuvastatin in Period 2, 5 and 8		Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8
Tmax of Rosuvastatin in Period 2, 5 and 8		Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8
t1/2 of Rosuvastatin in Period 2, 5 and 8	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.	Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8
Vz/F of Rosuvastatin in Period 2, 5 and 8	Vz/F was calculated as dose/(AUCinf*kel). AUCinf was calculated as AUClast + (Clast/kel), where AUClast is area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast), Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel is first-order elimination rate constant.	Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8
CL/F of Rosuvastatin in Period 2, 5 and 8	CL/F was calculated as dose/AUCinf. AUCinf was calculated as AUClast + (Clast/kel), where AUClast is area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast), Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis and kel is first-order elimination rate constant.	Pre-dose (0 hour), 1, 2, 3, 4, 5, 6, 8, 10, 14, 24, 48, 72 and 96 hours post dose of ROSU on Day 1 of Period 2, 5 and 8
Area Under the Concentration-Time Curve From Time 0 to Time 24 Hours (AUC24) of PF-07081532 When Co-administered With DE and ROSU in Period 4 and 8 Respectively		Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 14 and 24 hours post dose of PF-07081532 in Period 4 and 8
Cmax of PF-07081532 When Co-administered With DE and ROSU in Period 4 and 8 Respectively		Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 14 and 24 hours post dose of PF-07081532 in Period 4 and 8
Tmax of PF-07081532 When Co-administered With DE and ROSU in Period 4 and 8 Respectively		Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 14 and 24 hours post dose of PF-07081532 in Period 4 and 8

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): March 27, 2023
• Primary Completion (Actual): September 11, 2023
• Study Completion (Actual): September 11, 2023

Study Registration Dates

• First Submitted: March 15, 2023
• First Submitted That Met QC Criteria: March 15, 2023
• First Posted (Actual): March 28, 2023

Study Record Updates

• Last Update Posted (Actual): November 15, 2024
• Last Update Submitted That Met QC Criteria: September 9, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Physiological Effects of Drugs; Rosuvastatin; Anticoagulant; Molecular Mechanisms of Pharmacological Action; Dabigatran etexitlate; BCRP substrate; P-gp substrate; Antihyperlipidemic
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Antimetabolites; Anticoagulants; Antithrombins; Serine Proteinase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dabigatran; Rosuvastatin Calcium
• Other Study ID Numbers: C3991047

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