Effect of Tepotinib on the PK of the P-gp Substrate Dabigatran Etexilate

Merck KGaA, Darmstadt, Germany20 enrolled

Overview

This study investigated the effect of Tepotinib on the pharmacokinetics (PK) of the p-glycoprotein (P-gp) probe substrate Dabigatran etexilate.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

Dabigatran EtexilateDRUG

Participants received single oral dose of Dabigatran etexilate on Day 1 of Treatment period 1 and co-administration of Dabigatran with Tepotinib on Day 8 of Treatment period 2.

TepotinibDRUG

Participants received single oral dose of Tepotinib for 8 days in Treatment period 2.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 44 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy participants of non-child bearing potential * Body weight between 50 to 100 kilogram (kg) * Body mass index (BMI) between 18.5 and 29.9 kilogram per meter square (kg/m\^2) * A male participant must agree to use and to have his female partner of childbearing potential to use highly effective method of contraception * Participant must have given written informed consent before any study-related activities * All values for hematology, coagulation, and biochemistry tests of blood and urinalysis are within the normal range. Minor (solitary) non-clinically relevant deviation(s) are allowed as judged by the Investigator * Other protocol defined inclusion criteria could apply Exclusion Criteria: * Participation in a clinical study within 60 days prior to first drug administration * Whole blood donation or loss of \> 450 milliliter (mL) within 60 days prior to first drug administration * Any surgical or medical condition, or any other significant disease that could interfere with the study objectives, conduct, or evaluation * Supine systolic blood pressure (SBP) greater than (\>) 140 millimeter of mercury (mmHg) or less than (\<) 90 mmHg, diastolic blood pressure (DBP) \> 90 or \< 50 mmHg, and pulse rate \> 90 or \<50 beats per minute (bpm) at Screening and at admission on Day-1. * 12-Lead electrocardiograms (ECG) showing a corrected QT interval per Fridericia's formula (QTcF) \> 450 milliseconds (ms), PR \> 215 ms, or QRS \> 120 ms (at Screening) * Creatinine clearance estimated glomerular filtration rate (eGFR) \< 90 milliliter per minute (mL/min) (at Screening) * Participants with gall bladder removal or other relevant surgery of gastrointestinal tract * History of any malignancy * History of epilepsy * Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or excipients * Participants who in the Investigator's judgment were perceived as having an increased risk of bleeding * Positive screen for alcohol or drugs of abuse (at Screening and Day -1) * Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), and human immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at Screening) * Excessive consumption of xanthine-containing food or beverages before study drug administration until collection of last pharmacokinetic (PK) sample in each period (at Screening and Day -1) * Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives, before study drug administration * Smoker or former smoker who stopped smoking less than 6 months before the time of the Screening Visit * Intake of grapefruit, Seville orange, cranberry or juices of these 3 fruits, or St. John's Wort, from 14 days prior to Day -1 * Inability to communicate or cooperate with the Investigator * Other factors, which in the opinion of the Investigator may interfere with study conduct (at Screening and Day -1 of first Period only) * Legal incapacity or limited legal capacity * Participants kept in detention * Other protocol defined exclusion criteria could apply

Locations (1)

Nuvisan GmbH

Neu-Ulm, Germany

Outcomes

Primary Outcomes

Area Under Plasma Concentration-time Curve From Time Zero to Last Sampling Time (Tlast) at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Total Dabigatran

AUC0-t was calculated according to the mixed log linear trapezoidal rule.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Dabigatran

AUC0-inf was calculated as AUC0-t plus (+) AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastpred/Lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log-linear regression line for Lambda z determination at which the measured plasma concentration is at or above Lower limit of quantification (LLOQ).

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran

Cmax was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Secondary Outcomes

Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran

Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8

Elimination Half Life (t1/2) of Total Dabigatran

Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.

Data from ClinicalTrials.gov

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