Clinical trial NCT03628339: Effect of Tepotinib on PK of CYP3A Substrate Midazolam
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Tepotinib
Midazolam
Cytochrome P450
Pharmacokinetics
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2018-08-14
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 44
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: This is a single sequence cross-over trial.
Primary purpose: OTHER

Brief summary: 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.


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)
* 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

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 Midazolam
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam
timeFrame: 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 outcomes:
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam)
timeFrame: 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
measure: Elimination Half Life (t1/2) of Midazolam and Midazolam Metabolite (1-Hydroxymidazolam)
timeFrame: 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
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 Midazolam Metabolite (1-Hydroxymidazolam)
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Midazolam Metabolite (1-Hydroxymidazolam)
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Midazolam Metabolite (1-Hydroxymidazolam)
timeFrame: 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
measure: Metabolic Ratio of Midazolam and Midazolam Metabolite (1-hydroxymidazolam)
timeFrame: 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
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death
timeFrame: Baseline (Day 1 of treatment period 1) up to the End of Trial visit (Day 20)
measure: Number of Participants With Clinically Significant Changes in Laboratory Values
timeFrame: From Screening up to the End of Trial visit (Day 20)
measure: Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG)
timeFrame: Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20)
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20)
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: