Effect of a Proton Pump Inhibitor on the PK of Tepotinib

Phase I, Open-label, Three-Period Crossover Study to Investigate the Effect of a Proton Pump Inhibitor (Omeprazole) on the PK of Tepotinib in Healthy Subjects

This study was investigated in healthy participants (i) the effect of omeprazole (proton pump inhibitor) co-administration on the single dose pharmacokinetics (PK) of tepotinib under fed conditions, and (ii) the effect of food on the single dose PK of tepotinib after co-administration of omeprazole and tepotinib. Furthermore, the study assessed the safety and tolerability of tepotinib alone and upon co-administration of omeprazole.

Study Overview

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

• 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 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy participants of non-child bearing potential
• Body mass index (BMI) between 18.5 and 29.9 kilogram per meter square (kg/m^2)
• Body weight between 50 to 100 kilogram (kg)
• 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: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1: Treatment A-B-C; Participants received single oral dose of 500 milligrams (mg) of Tepotinib alone in fed state on Day 1 of Treatment period 1 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 2 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment B) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 3 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment C). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.	Drug: Tepotinib; Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C.; Drug: Omeprazole; Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.
Experimental: Sequence 2: Treatment A-C-B; Participants received single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 1 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 2 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment C) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 3 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment B). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.	Drug: Tepotinib; Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C.; Drug: Omeprazole; Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.
Experimental: Sequence 3: Treatment B-A-C; Participants received single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 1 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment B) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 2 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 3 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment C). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.	Drug: Tepotinib; Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C.; Drug: Omeprazole; Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.
Experimental: Sequence 4: Treatment B-C-A; Participants received single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 1 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment B) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 2 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment C) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 3 (Treatment A). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.	Drug: Tepotinib; Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C.; Drug: Omeprazole; Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.
Experimental: Sequence 5: Treatment C-A-B; Participants received single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 1 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment C) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 2 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 3 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment B). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.	Drug: Tepotinib; Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C.; Drug: Omeprazole; Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.
Experimental: Sequence 6: Treatment C-B-A; Participants received single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 1 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment C) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 2 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment B) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 3 (Treatment A). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.	Drug: Tepotinib; Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C.; Drug: Omeprazole; Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Tepotinib in Treatment A and Treatment C	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment C)
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib in Treatment A and Treatment C	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/Lambda z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment C)
Maximum Observed Plasma Concentration (Cmax) of Tepotinib in Treatment A and Treatment C	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment C)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Tepotinib in Treatment B	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 5 for Treatment B
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib in Treatment B	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/Lambda z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 5 for Treatment B
Maximum Observed Plasma Concentration (Cmax) of Tepotinib in Treatment B	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 5 for Treatment B
Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib in Treatments A, B and C	Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment B and C)
Apparent Terminal Half-life (t1/2) of Tepotinib in Treatments A, B and C	Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by lambda z.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment B and C)
Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of Tepotinib in Treatments A, B and C	Time prior to the first measurable (non-zero) concentration; calculated as last time point at which the concentration is less than (<) Lower Limit of Quantification (LLOQ) before the occurrence of the first quantifiable concentration.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment B and C)
Apparent Total Body Clearance (CL/f) of Tepotinib in Treatments A, B and C	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment B and C)
Apparent Volume of Distribution During Terminal Phase (Vz/f) of Tepotinib in Treatments A, B and C	Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing.	Pre-dose, 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hour post-dose on Day 1 (for Treatment A) and on Day 5 (for Treatment B and C)
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether/not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE 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. An AE was considered as 'treatment emergent' if it occurred after the first drug administration or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both serious TEAEs and non-serious TEAEs.	Baseline up to Day 7 for Treatment A and up to Day 11 for Treatment B and C
Number of Participants With Clinically Significant Changes in Laboratory Parameters, 12-lead Electrocardiogram (ECG) Findings and Vital Signs	The laboratory measurements included hematology, biochemistry, virology, drugs of abuse, hormones, and urinalysis. ECG recordings included PR, QRS, RR, QT and corrected QT intervals (QTcF). Vital sign assessment included blood pressure, pulse rate, body temperature. Number of participants with clinically significant abnormalities in laboratory parameters, 12-lead ECG findings, vital signs were reported. Clinically significance was decided by investigator.	Baseline up to Day 4 for Treatment A and up to Day 8 for Treatment B and C

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): May 14, 2018
• Primary Completion (Actual): July 2, 2018
• Study Completion (Actual): July 2, 2018

Study Registration Dates

• First Submitted: May 9, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 22, 2018

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Non-small cell lung cancer (NSCLC); Tepotinib; Omeprazole; Proton Pump Inhibitor
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole; Tepotinib
• Other Study ID Numbers: MS200095_0039; 2017-002832-18 (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