Healthy
Conditions
Keywords
Clinical pharmacology, Metabolite, Induction of metabolism
Brief summary
The purpose of this study was to assess the effect of multiple doses of itraconazole on single dose tepotinib pharmacokinetics in healthy participants. Study details include: Study Duration: up to 48 days Treatment Duration: single dose of tepotinib on Days 1 and 12, 11 days of treatment with itraconazole (Days 8 to 18) Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 11 to 15, ambulatory daily visits from Days 5 to 10 and 16 to 20
Interventions
DRUGTepotinib (HydroChloride hydrate)
Participants received Tepotinib (Hydrochloride hydrate) Film-coated tablet with food on Day 1 and 12 in the morning.
DRUGItraconazole
Participants received Itraconazole Hard-gelatin capsule with food once daily at the same time in the morning from Day 8 to Day 18; on Day 12 itraconazole is administered concomitantly with tepotinib.
Sponsors
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single sequence cross-over trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Overtly healthy participants as determined by medical evaluation, including no clinically significant abnormality identified by medical history, cardiac monitoring, physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion at Screening and Day -1 * Had a body weight within 50 and 100 kilogram (inclusive) and Body Mass Index (BMI) within the range greater than or equal (\>=) 18.5 and less than or equal to (\<=) 29.9 kilogram per meter square (inclusive) at Screening * Male or female (not a Women of childbearing potential \[WOCBP\]). The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below: * Contraceptive use will be consistent with local regulations on contraception methods for those participating in clinical studies. Male Participants: Agree to the following during the study intervention period and for at least 1 week after the last dose of study intervention: Refrain from donating fresh and unwashed sperm PLUS, either: Abstain from intercourse with a WOCBP.OR Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and instruct her to use a highly effective contraceptive method with a failure rate of \< 1percent (%) per year * Not a WOCBP, confirmed at Screening, by fulfilling at least 1 of the following criteria: Females who are postmenopausal and documentation of irreversible surgical sterilization by hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy * Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and this protocol * All values for hematology, coagulation, and biochemistry tests of blood and urinalysis within the normal range (at Screening and Day -1) * Other protocol defined inclusion criteria could apply
Exclusion criteria
* History or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation * Participants with gall bladder removal or other relevant surgery of gastrointestinal tract (appendectomy is not considered as relevant) * History of any malignancy except for adequately treated superficial basal cell carcinoma * History of epilepsy * Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or excipients; history of anaphylaxis to drugs or serious allergic reactions leading to hospitalization or any other allergy reaction in general, which the Investigator considers may affect the safety of the participant and/or outcome of the study * Any condition, including findings in the laboratory tests, medical history, or other Screening assessments, that in the opinion of the Investigator constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study's objectives, conduct, or evaluation * Use of any prescribed medicine or over-the-counter drug or dietary supplement, including herbal remedies, vitamins, and minerals, antacids and dietary supplements such as fish oils within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to the first administration of study intervention * Participation in the treatment phase of a clinical study within 60 days or 5 half-lives after last dosing of the previous study drug, whatever is longer, before administration of study drug * Contraindication to itraconazole: ventricular dysfunction such as congestive heart failure or a history of congestive heart failure, drug interactions (example: co-administration of a number of CYP3A4 substrates), pregnancy, hypersensitivity to itraconazole * Donation or loss of more than 450 milliliter (mL) of blood in the 60 days prior to Screening, donation of plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening * Consumption of alcohol from 48 hours prior to first administration of study intervention * Smoker (cigarettes, pipes, cigars, or others) or former smoker who stopped smoking for less than 6 months before the time of the Screening visit * Inability to communicate or cooperate with the Investigator (example: language problem, illiteracy, poor mental status) or to comply with the requirements of the entire study, including dietary restrictions * Other factors, which in the opinion of the Investigator may interfere with study conduct * Legal incapacity or limited legal capacity * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | Predose up to 168 hours post dose | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination. |
| Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib | Predose up to 168 hours post dose | The AUC from time zero (= dosing time) to time of the last quantifiable concentration (tlast). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite | Predose up to 168 hours post dose | Cmax was obtained directly from the concentration versus time curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Baseline (Day 1) up to follow up (assessed up to Day 20) | Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs. |
| Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | Predose up to 168 hours post dose | CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 | Baseline (Day 1) up to follow up (assessed up to Day 20) | An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence 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. TEAE's were those events with onset dates on or after the first administration of study intervention. Severity of abnormalities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version \[24.1\]. grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | Predose up to 168 hours post dose | The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. |
| Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | Predose up to 168 hours post dose | t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half. |
| Apparent Volume of Distribution (Vz/f) for Tepotinib | Predose up to 168 hours post dose | Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration. |
| Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Baseline (Day 1) up to follow up (assessed up to Day 20) | Laboratory investigation included hematology, biochemistry and urinalysis. Clinically meaningful was decided by the investigator. Number of participants with clinically meaningful change from baseline in laboratory values were reported. |
| Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | Baseline (Day 1) up to follow up (assessed up to Day 20) | The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Significance was decided by the investigator. Number of participants with clinically meaningful change from baseline in ECG parameters were reported. |
Countries
Germany
Participant flow
Pre-assignment details
A total of 44 participants were screened, out of which 18 participants received the study drug.
Participants by arm
| Arm | Count |
|---|---|
| Tepotinib and Itraconazole Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Tepotinib and Itraconazole |
|---|---|
| Age, Continuous | 43 Years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 14 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib
The AUC from time zero (= dosing time) to time of the last quantifiable concentration (tlast). Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Predose up to 168 hours post dose
Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib | 18300 h*ng/mL | Geometric Coefficient of Variation 27.9 |
| Tepotinib and Itraconazole | Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib | 21391 h*ng/mL | Geometric Coefficient of Variation 30.2 |
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination.
Time frame: Predose up to 168 hours post dose
Population: Pharmacokinetic (PK) analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | 18927 hours* nanograms per milliliter(h*ng/mL) | Geometric Coefficient of Variation 28.2 |
| Tepotinib and Itraconazole | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | 23158 hours* nanograms per milliliter(h*ng/mL) | Geometric Coefficient of Variation 29.9 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite
Cmax was obtained directly from the concentration versus time curve.
Time frame: Predose up to 168 hours post dose
Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite | 308 nanogram per mililiter (ng/mL) | Geometric Coefficient of Variation 24.8 |
| Tepotinib and Itraconazole | Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite | 313 nanogram per mililiter (ng/mL) | Geometric Coefficient of Variation 28.2 |
Secondary
Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma
t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half.
Time frame: Predose up to 168 hours post dose
Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | 32.1 hours | Geometric Coefficient of Variation 7.8 |
| Tepotinib and Itraconazole | Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | 40.9 hours | Geometric Coefficient of Variation 19.2 |
Secondary
Apparent Volume of Distribution (Vz/f) for Tepotinib
Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration.
Time frame: Predose up to 168 hours post dose
Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Apparent Volume of Distribution (Vz/f) for Tepotinib | 1102 liters | Geometric Coefficient of Variation 29.4 |
| Tepotinib and Itraconazole | Apparent Volume of Distribution (Vz/f) for Tepotinib | 1148 liters | Geometric Coefficient of Variation 34.3 |
Secondary
Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Significance was decided by the investigator. Number of participants with clinically meaningful change from baseline in ECG parameters were reported.
Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)
Population: SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib | Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | 0 Participants |
Secondary
Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values
Laboratory investigation included hematology, biochemistry and urinalysis. Clinically meaningful was decided by the investigator. Number of participants with clinically meaningful change from baseline in laboratory values were reported.
Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)
Population: SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tepotinib | Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Hematology | 0 Participants |
| Tepotinib | Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Biochemistry | 0 Participants |
| Tepotinib | Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Urinalysis | 0 Participants |
Secondary
Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs.
Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)
Population: SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib | Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3
An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence 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. TEAE's were those events with onset dates on or after the first administration of study intervention. Severity of abnormalities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version \[24.1\]. grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE
Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)
Population: The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tepotinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 | Any TEAE | 14 Participants |
| Tepotinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 | Any serious TEAE | 0 Participants |
| Tepotinib | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 | Any TEAE of Grade ≥ 3 (severe) | 0 Participants |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib
The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Time frame: Predose up to 168 hours post dose
Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tepotinib | Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | 8.00 hours |
| Tepotinib and Itraconazole | Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | 8.00 hours |
Secondary
Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib
CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Predose up to 168 hours post dose
Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | 23.8 liter/hour | Geometric Coefficient of Variation 28.2 |
| Tepotinib and Itraconazole | Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | 19.4 liter/hour | Geometric Coefficient of Variation 29.9 |