Effect of Tepotinib on the Pharmacokinetics (PK) of the P-glycoprotein (P-gp) Substrate Dabigatran Etexilate

Sponsor

Merck KGaA, Darmstadt, Germany (Industry)

Overall Status

Completed

CT.gov ID

NCT03492437

Collaborator

(none)

Enrollment

Location

Arm

3.4

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Dabigatran Etexilate Drug: Tepotinib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Phase I, Open-label, Single Sequence, Two-Period Study to Evaluate the Effect of Tepotinib on P-Glycoprotein by Investigating the Pharmacokinetics of the P-Glycoprotein Probe Substrate Dabigatran Etexilate in Healthy Subjects

Actual Study Start Date :

May 17, 2018

Actual Primary Completion Date :

Aug 27, 2018

Actual Study Completion Date :

Aug 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dabigatran, Then Tepotinib followed by Dabigatran+Tepotinib Dabigatran etexilate in treatment period 1 followed by tepotinib alone for 7 days and then tepotinib co-administered with Dabigatran in treatment period 2. Two treatment periods will be separated by a 3-day wash-out period.	Drug: Dabigatran Etexilate Participants will receive 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. Drug: Tepotinib Participants will receive single oral dose of Tepotinib for 8 days in Treatment period 2.

Arm

Intervention/Treatment

Experimental: Dabigatran, Then Tepotinib followed by Dabigatran+Tepotinib

Dabigatran etexilate in treatment period 1 followed by tepotinib alone for 7 days and then tepotinib co-administered with Dabigatran in treatment period 2. Two treatment periods will be separated by a 3-day wash-out period.

Drug: Dabigatran Etexilate

Participants will receive 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.

Drug: Tepotinib

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

Outcome Measures

Primary Outcome Measures

Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Dabigatran [Pre-dose up to 72 hours post-dose]
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Dabigatran [Pre-dose up to 72 hours post-dose]
Maximum Observed Plasma Concentration (Cmax) of Dabigatran [Pre-dose up to 72 hours post-dose]

Secondary Outcome Measures

Time to Reach Maximum Plasma Concentration (Tmax) of Dabigatran [Pre-dose up to 72 hours post-dose]
Elimination Half Time (t1/2) of Dabigatran [Pre-dose up to 72 hours post-dose]
Apparent Clearance (CL/f) of Dabigatran [Pre-dose up to 72 hours post-dose]
Apparent Volume of Distribution During Terminal Phase (Vz/f) of Dabigatran [Pre-dose up to 72 hours post-dose]
Percentage of Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Dabigatran [Pre-dose up to 72 hours post-dose]
Occurrence of Treatment-emergent Adverse Events (TEAEs) [Baseline up to Day 15]
Number of Participants With Clinically Significant Changes in Laboratory Assessments, 12-lead Electrocardiogram (ECG) Findings and Vital Signs [Baseline up to Day 15]
Number of participants with clinically significant changes will be reported.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 44 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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