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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
16
Dabigatran etexilate (DE) as oral capsule
Rosuvastatin as oral tablet
PF-07081532 as oral tablets
Qps-Mra, Llc
South Miami, Florida, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
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