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

Phase 1

Terminated

Conditions: Healthy

Interventions: Drug: Dabigatran etexilate (DE)
Drug: Rosuvastatin
Drug: PF-07081532

Registration Number: NCT05788328

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 16

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
Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at Screening
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
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
History of depressive disorder or history of other severe psychiatric disorders within the last 2 years from Screening
Any lifetime history of a suicide attempt
Known medical history of active liver disease, or prior known drug-induced liver injury
History of HIV infection
Recent history of bleeding, or risks of bleeding, or abnormal coagulation test (INR >1.3) result at Screening
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 may affect participant safety or interpretation of study result
Participants with clinical laboratory test abnormalities at Screening

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Period 4	PF-07081532	Participants will receive PF-07081532 daily and DE as a single dose
Period 4	Dabigatran etexilate (DE)	Participants will receive PF-07081532 daily and DE as a single dose
Period 1	Dabigatran etexilate (DE)	Participants will receive dabagatrin etexilate (DE) as a single dose
Period 3	PF-07081532	Participants will receive PF-07081532 daily titrated
Period 5	PF-07081532	Participants will receive PF-07081532 daily and rosuvastatin as a single dose
Period 6	PF-07081532	Participants will receive PF-07081532 daily titrated
Period 7	Dabigatran etexilate (DE)	Participants will receive PF-07081532 daily and DE as a single dose
Period 7	PF-07081532	Participants will receive PF-07081532 daily and DE as a single dose
Period 8	PF-07081532	Participants will receive PF-07081532 daily and rosuvastatin as a single dose
Period 2	Rosuvastatin	Participants will receive rosuvastatin as a single dose
Period 5	Rosuvastatin	Participants will receive PF-07081532 daily and rosuvastatin as a single dose
Period 8	Rosuvastatin	Participants will receive PF-07081532 daily and rosuvastatin as a single dose

Primary Outcome Measures

Name	Time	Method
Area Under the Concentration-Time Curve From Time Zero (0) Extrapolated to Infinity (AUCinf) 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	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.
Area Under the Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUClast) 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	AUClast was determined using the linear/log trapezoidal method.
AUCinf 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	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.
AUClast 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	AUClast was determined using the linear/log trapezoidal method.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Treatment Emergent Adverse Events (TEAEs)- All Causalities	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality)	During treatment of the study (maximum up to 48 days)	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.
Number of Participants With Clinically Significant Vital Signs	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)	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.
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	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)	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.
Number of Participants According to Columbia-Suicide Severity Rating Scale (C-SSRS)	From first dose of study drug up to 28-35 days post last dose of study intervention (maximum up to 76-83 days)	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.
Number of Participants According to Patient Health Questionnaire-9 (PHQ-9) Classification	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	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.
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	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	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.
Apparent Volume of Distribution (Vz/F) 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	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.
Apparent Oral Clearance (CL/F) 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	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.
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	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 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.
Vz/F 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	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.
CL/F 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	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.
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