Effect of Tepotinib on the PK of the P-gp Substrate Dabigatran Etexilate

Healthy Clinical Trial

Official title:

Phase I, Open-label, Single Sequence, Two-Period Study to Evaluate the Effect of Tepotinib on P-gp by Investigating the PK of the P-gp Probe Substrate Dabigatran Etexilate in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03492437
• Other study ID #: MS200095_0032
• Secondary ID: 2017-004074-34
• Status: Completed
• Phase: Phase 1
• Start date: May 17, 2018
• Est. completion date: August 27, 2018

Study information

• Verified date: August 2023
• Source: Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study investigated the effect of Tepotinib on the pharmacokinetics (PK) of the p-glycoprotein (P-gp) probe substrate Dabigatran etexilate.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: August 27, 2018
• Est. primary completion date: August 27, 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)
• A male participant must agree to use and to have his female partner of childbearing potential to use highly effective method of contraception
• Participant must have given written informed consent before any study-related activities
• All values for hematology, coagulation, and biochemistry tests of blood and urinalysis are within the normal range. Minor (solitary) non-clinically relevant deviation(s) are allowed as judged by the Investigator
• 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 > 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
• Supine systolic blood pressure (SBP) greater than (>) 140 millimeter of mercury (mmHg) or less than (<) 90 mmHg, diastolic blood pressure (DBP) > 90 or < 50 mmHg, and pulse rate > 90 or <50 beats per minute (bpm) at Screening and at admission on Day-1.
• 12-Lead electrocardiograms (ECG) showing a corrected QT interval per Fridericia's formula (QTcF) > 450 milliseconds (ms), PR > 215 ms, or QRS > 120 ms (at Screening)
• Creatinine clearance estimated glomerular filtration rate (eGFR) < 90 milliliter per minute (mL/min) (at Screening)
• Participants with gall bladder removal or other relevant surgery of gastrointestinal tract
• History of any malignancy
• History of epilepsy
• Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or excipients
• Participants who in the Investigator's judgment were perceived as having an increased risk of bleeding
• Positive screen for alcohol or drugs of abuse (at Screening and Day -1)
• Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), and human immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at Screening)
• Excessive consumption of xanthine-containing food or beverages before study drug administration until collection of last pharmacokinetic (PK) sample in each period (at Screening and Day -1)
• Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives, before study drug administration
• Smoker or former smoker who stopped smoking less than 6 months before the time of the Screening Visit
• Intake of grapefruit, Seville orange, cranberry or juices of these 3 fruits, or St. John's Wort, from 14 days prior to Day -1
• Inability to communicate or cooperate with the Investigator
• Other factors, which in the opinion of the Investigator may interfere with study conduct (at Screening and Day -1 of first Period only)
• Legal incapacity or limited legal capacity
• Participants kept in detention
• Other protocol defined exclusion criteria could apply

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Dabigatran Etexilate
Participants received single oral dose of Dabigatran etexilate on Day 1 of Treatment period 1 and co-administration of Dabigatran with Tepotinib on Day 8 of Treatment period 2.
• Tepotinib
Participants received single oral dose of Tepotinib for 8 days 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 Total Dabigatran	AUC0-t was calculated according to the mixed log linear trapezoidal rule.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Primary	Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total Dabigatran	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, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Primary	Maximum Observed Plasma Concentration (Cmax) of Total Dabigatran	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Secondary	Time to Reach Maximum Plasma Concentration (Tmax) of Total Dabigatran	Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Secondary	Elimination Half Life (t1/2) of Total Dabigatran	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, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Secondary	Apparent Clearance (CL/f) of Total Dabigatran	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Secondary	Apparent Volume of Distribution During Terminal Phase (Vz/f) of Total Dabigatran	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/f after oral dose was influenced by the fraction absorbed.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Secondary	Percentage of Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUC0-inf) Obtained by Extrapolation (AUCextra%) of Total Dabigatran	The AUC from time tlast extrapolated to infinity given as percentage of AUC0-inf. AUCextra% = (AUCextra /AUC0-inf)*100.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours Post-dose on Day 1 and Day 8
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	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. TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs.	Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Secondary	Number of Participants With Clinically Significant Changes in Laboratory Values	Number of participants with clinically significant change in laboratory values were reported. Clinical significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, virology, drugs of abuse, hormones, urinalysis, and coagulation.	Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Secondary	Number of Participants With Clinically Significant Changes in 12-lead Electrocardiogram (ECG) Findings	Number of participants with clinically significant change in 12-lead ECG were reported. Clinical significance was decided by the investigator. The 12-lead ECGs were recorded after the participant have rested for at least 5 minutes in supine position.	Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2
Secondary	Number of Participants With Clinically Significant Changes in Vital Signs	Number of participants with clinically significant change in vital signs were reported. Clinical significance was decided by the investigator. Vital signs included body temperature, blood pressure, and pulse rate.	Screening up to Day 4 in Period 1; Day 1 up to Day 15 in Period 2

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