Tepotinib Drug-Drug Interaction Study With Carbamazepine in Healthy Participants

Phase I, Open-Label, Single-sequence, Cross-Over Study of the Effect of Multiple Doses of Carbamazepine on Single-Dose Tepotinib Pharmacokinetics in Healthy Participants

The purpose of this study was to assess the effect of multiple doses of carbamazepine on single- dose tepotinib pharmacokinetics in healthy participants. Study details include: Study Duration: up to about 10 weeks; Treatment Duration: single dose of tepotinib on Days 1 and 26, 25 days of treatment with carbamazepine (Days 8 to 32); Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 25 to 29, ambulatory daily visits from Days 5 to 24 and 30 to 33, and one ambulatory visit on Day 39.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Tepotinib; Drug: Carbamazepine

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neu-Ulm, Germany
    • Nuvisan GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Overtly healthy participants as determined by medical evaluation, including no clinically significant abnormality identified by medical history, cardiac monitoring, physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion at Screening and Day -1
• Had a body weight within 50 and 100 kilogram (inclusive) and Body Mass Index (BMI) within the range greater than or equal (>=) 18.5 and less than or equal to (<=) 29.9 kilogram per meter square (inclusive) at Screening
• Male or female (not a Women of childbearing potential [WOCBP]). The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below:
• Contraceptive use was consistent with local regulations on contraception methods for those participating in clinical studies. Male Participants: Agree to the following during the study intervention period and for at least 1 week after the last dose of study intervention: Refrain from donating fresh and unwashed sperm PLUS (+), either: Abstain from intercourse with a WOCBP.OR Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and instruct her to use a highly effective contraceptive method with a failure rate of < 1percent (%) per year
• Since a condom may break or leak. Not a WOCBP, confirmed at Screening, by fulfilling at least 1 of the following criteria: Females who are postmenopausal (age-related amenorrhea >= 12 consecutive months and increased Follicle-stimulating hormone (FSH)
• Documentation of irreversible surgical sterilization by hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• History or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation
• Participants with gall bladder removal or other relevant surgery of gastrointestinal tract (appendectomy is not considered as relevant)
• History of any malignancy except for adequately treated superficial basal cell carcinoma
• History of epilepsy
• Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or excipients; history of anaphylaxis to drugs or serious allergic reactions leading to hospitalization or any other allergy reaction in general, which the Investigator considers may affect the safety of the participant and/or outcome of the study
• Any condition, including findings in the laboratory tests, medical history, or other Screening assessments, that in the opinion of the Investigator constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study's objectives, conduct, or evaluation
• Use of any prescribed medicine or over-the-counter drug or dietary supplement, including herbal remedies, vitamins, and minerals, antacids and dietary supplements such as fish oils within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to the first administration of study intervention
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tepotinib then Carbamazepine; Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 26 in the morning under fed state followed by Carbamazepine 100, 200 or 300mg oral dose under fed state twice daily at the same time each day in the morning and evening from Days 8 to Day 32	Drug: Tepotinib; Participants received Tepotinib hydrochloride hydrate film-coated tablet once daily with food on Day 1 and Day 26 in the morning.; Drug: Carbamazepine; Carbamazepine 100 mg twice daily at Day 8 and 9, 200 mg twice daily at Day 10 and 11, 300 mg twice daily from Day 12 to 32.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib	The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination.	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib	The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Maximum Observed Plasma Concentration (Cmax) of Tepotinib	Cmax was obtained directly from the concentration versus time curve.	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3	An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE's were those events with onset dates on or after the first administration of study intervention. Severity of abnormalities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version [24.1]. grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE	Baseline (Day 1) up to 10 Weeks
Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values	Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, urinalysis, and coagulation.	Baseline (Day 1) up to 10 Weeks
Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)	Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula.	Baseline (Day 1) up to 10 Weeks
Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs	Number of participants with clinically significant change from baseline in vital signs. Clinical Significance was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.	Baseline (Day 1) up to 10 Weeks
Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib	CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Apparent Volume of Distribution (Vz/f) for Tepotinib	Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration.	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib	The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma	t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half.	Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose

Collaborators and Investigators

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2021
• Primary Completion (Actual): May 6, 2022
• Study Completion (Actual): May 6, 2022

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: January 10, 2022
• First Posted (Actual): January 28, 2022

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Metabolite; Clinical pharmacology; Induction of metabolism
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anticonvulsants; Sodium Channel Blockers; Antimanic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Carbamazepine; Tepotinib
• Other Study ID Numbers: MS200095_0051; 2021-003546-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany, will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No