Effect of Tepotinib on PK of CYP3A Substrate Midazolam

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03628339
• Other study ID #: MS200095_0030
• Secondary ID: 2017-005055-92
• Status: Completed
• Phase: Phase 1
• Start date: August 20, 2018
• Est. completion date: October 30, 2018

Study information

• Verified date: September 2022
• Source: Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: October 30, 2018
• Est. primary completion date: October 25, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 44 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

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.
• Tepotinib
Participants received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 in treatment period 2.

Locations

Country	Name	City	State
Germany	Nuvisan GmbH	Neu-Ulm

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA, Darmstadt, Germany

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External 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