Effect of Tepotinib on PK of CYP3A Substrate Midazolam

Phase 1, Open-label, Single Sequence, Two-Period Crossover Trial to Evaluate the Effect of Tepotinib on CYP3A by Investigating the PK of the CYP3A Substrate Midazolam in Healthy Subjects

The study investigated the effect of tepotinib on the pharmacokinetics (PK) of the Cytochrome P450 (CYP) 3A substrate midazolam determined from concentrations of midazolam and its main metabolite 1-hydroxymidazolam in healthy participants.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neu-Ulm, Germany, 89231
    • Nuvisan GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 44 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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)
• 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 greater than 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
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midazolam (Reference Treatment); Participants received single oral dose of 7.5 milligrams (mg) midazolam tablet on Day 1 of treatment period 1. The washout period between midazolam administrations in Period 1 and Period 2 was 12 days.	Drug: Midazolam; Participant received single oral dose of 7.5 mg midazolam tablet on Day 1 of treatment period 1 and Day 11 in treatment period 2.
Experimental: Tepotinib + Midazolam (Test Treatment); All participants who received 7.5 mg midazolam tablet in treatment period 1 received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in treatment period 2.	Drug: Midazolam; Participant received single oral dose of 7.5 mg midazolam tablet on Day 1 of treatment period 1 and Day 11 in treatment period 2.; Drug: Tepotinib; Participants received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 in treatment period 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Midazolam	AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam	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, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Maximum Observed Plasma Concentration (Cmax) of Midazolam	Cmax was obtained directly from concentration versus time curve.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reach Maximum Plasma Concentration (Tmax) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam)	Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Elimination Half Life (t1/2) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam)	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.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
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 Midazolam Metabolite (1-Hydroxymidazolam)	AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam Metabolite (1-Hydroxymidazolam)	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, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Maximum Observed Plasma Concentration (Cmax) of Midazolam Metabolite (1-Hydroxymidazolam)	Cmax was obtained directly from concentration versus time curve.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Metabolic Ratio of Midazolam and Midazolam Metabolite (1-hydroxymidazolam)	Metabolic ratio was calculated as AUC 0-infinity of midazolam divided by AUC 0-infinity of 1-hydroxymidazolam.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death	Adverse event (AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event (SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs.	Baseline (Day 1 of treatment period 1) up to the End of Trial visit (Day 20)
Number of Participants With Clinically Significant Changes in Laboratory Values	Number of participants with clinically significant changes in laboratory values were reported. Clinical significance was decided by the investigator. Laboratory investigation included hematology and urinalysis.	From Screening up to the End of Trial visit (Day 20)
Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG)	Number of participants with clinically significant changes in 12-lead ECG were reported. Clinical significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minute in supine position.	Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20)
Number of Participants With Clinically Significant Changes in Vital Signs	Number of participants with clinically significant changes in vital signs were reported. Clinical significance was decided by Investigator. Vital signs included body temperature, blood pressure and pulse rate.	Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20)

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• 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)
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2018
• Primary Completion (Actual): October 25, 2018
• Study Completion (Actual): October 30, 2018

Study Registration Dates

• First Submitted: August 9, 2018
• First Submitted That Met QC Criteria: August 9, 2018
• First Posted (Actual): August 14, 2018

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Midazolam; Tepotinib; Cytochrome P450
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antineoplastic Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Tepotinib
• Other Study ID Numbers: MS200095_0030; 2017-005055-92 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No