Clinical trial NCT03492437: Effect of Tepotinib on the PK of the P-gp Substrate Dabigatran Etexilate
Official title: Phase I, Open-label, Single Sequence, Two-Period Study to Evaluate the Effect of Tepotinib on P-gp by Investigating the PK of the P-gp Probe Substrate Dabigatran Etexilate in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Non-small cell lung cancer (NSCLC)
P-glycoprotein
Tepotinib
Dabigatran Etexilate
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2018-04-10
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 44
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: CROSSOVER
Primary purpose: OTHER

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


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Dabigatran
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran
timeFrame: 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:
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran
timeFrame: 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
measure: Elimination Half Life (t1/2) of Total Dabigatran
timeFrame: 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
measure: Apparent Clearance (CL/f) of Total Dabigatran
timeFrame: 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
measure: Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran
timeFrame: 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
measure: Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran
timeFrame: 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
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
measure: Number of Participants With Clinically Significant Changes in Laboratory Values
timeFrame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
measure: Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Findings
timeFrame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Other outcomes:
Locations:
city: Neu-Ulm
country: Germany
facility: Nuvisan GmbH
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: