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

NCT03492437 | Completed Phase 1 Results

• 2 other identifiers: MS200095_00322017-004074-34
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Healthy

Keywords

Non-small cell lung cancer (NSCLC); P-glycoprotein; Tepotinib; Dabigatran Etexilate

Outcome Measures

Primary Outcomes (3)

• 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.

  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).

  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.

  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 (9)

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

  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

  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

• Apparent Clearance (CL/f) of Total Dabigatran

  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

• Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran

  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

• Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran

  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

Study Arms (2)

Dabigatran Etexilate

EXPERIMENTAL

Drug: Dabigatran Etexilate

Tepotinib + Dabigatran

EXPERIMENTAL

Drug: Dabigatran Etexilate; Drug: Tepotinib

Interventions

Dabigatran Etexilate DRUG

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.

Dabigatran Etexilate; Tepotinib + Dabigatran

Tepotinib DRUG

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

Tepotinib + Dabigatran

Eligibility Criteria

• Age: 18 Years - 44 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

Nuvisan GmbH

Neu-Ulm, 89231, Germany

Location

Related Publications (1)

• Yalkinoglu O, Becker A, Krebs-Brown A, Vetter C, Lupfert C, Perrin D, Heuer J, Biedert H, Hirt S, Bytyqi A, Bachmann A, Strotmann R. Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates. Invest New Drugs. 2023 Aug;41(4):596-605. doi: 10.1007/s10637-023-01378-z. Epub 2023 Jul 6.

  PMID: 37415001 DERIVED

Related Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts
• Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information)

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Dabigatran; tepotinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Communication Center
• Organization: Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 3, 2018
• First Posted: April 10, 2018
• Study Start: May 17, 2018
• Primary Completion: August 27, 2018
• Study Completion: August 27, 2018
• Last Updated: August 7, 2023
• Results First Posted: August 7, 2023

Record last verified: 2023-08

Locations

DE (1)