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 carbamazepine on single- dose tepotinib pharmacokinetics in healthy participants. Study details include: Study Duration: up to about 10 weeks; Treatment Duration: single dose of tepotinib on Days 1 and 26, 25 days of treatment with carbamazepine (Days 8 to 32); Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 25 to 29, ambulatory daily visits from Days 5 to 24 and 30 to 33, and one ambulatory visit on Day 39.
Interventions
DRUGTepotinib
Participants received Tepotinib hydrochloride hydrate film-coated tablet once daily with food on Day 1 and Day 26 in the morning.
DRUGCarbamazepine
Carbamazepine 100 mg twice daily at Day 8 and 9, 200 mg twice daily at Day 10 and 11, 300 mg twice daily from Day 12 to 32.
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 was 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 * Since a condom may break or leak. Not a WOCBP, confirmed at Screening, by fulfilling at least 1 of the following criteria: Females who are postmenopausal (age-related amenorrhea \>= 12 consecutive months and increased Follicle-stimulating hormone (FSH) * Documentation of irreversible surgical sterilization by hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy * 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 * 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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose | The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down). |
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose | Cmax was obtained directly from the concentration versus time curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 10 Weeks | 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 |
| Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Baseline (Day 1) up to 10 Weeks | Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, urinalysis, and coagulation. |
| Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) | Baseline (Day 1) up to 10 Weeks | Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance was decided by the investigator. 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. |
| Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs | Baseline (Day 1) up to 10 Weeks | Number of participants with clinically significant change from baseline in vital signs. Clinical Significance was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. |
| Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 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. |
| Apparent Volume of Distribution (Vz/f) for Tepotinib | Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose | Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration. |
| Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 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. |
Countries
Germany
Participant flow
Pre-assignment details
A total of 29 participants were screened, out of which 18 participants received the study drug.
Participants by arm
| Arm | Count |
|---|---|
| Tepotinib Then Carbamazepine Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 26 in the morning under fed state followed by Carbamazepine 100 mg twice daily at Day 8 and 9, 200 mg twice daily at Day 10 and 11, 300 mg twice daily from Day 12 to 32. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Tepotinib Then Carbamazepine |
|---|---|
| Age, Continuous | 43 Years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 00 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 18 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 7 / 18 | 13 / 14 | 7 / 14 |
| serious Total, serious adverse events | 0 / 18 | 0 / 14 | 0 / 14 |
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 the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| 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 | 24069 h*ng/mL | Geometric Coefficient of Variation 20.2 |
| Tepotinib Then Carbamazepine | Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib | 16272 h*ng/mL | Geometric Coefficient of Variation 13.4 |
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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | 25101 hours* nanograms per milliliter(h*ng/mL) | Geometric Coefficient of Variation 20.2 |
| Tepotinib Then Carbamazepine | Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib | 16738 hours* nanograms per milliliter(h*ng/mL) | Geometric Coefficient of Variation 14.1 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Tepotinib
Cmax was obtained directly from the concentration versus time curve.
Time frame: Predose 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Maximum Observed Plasma Concentration (Cmax) of Tepotinib | 414 nanogram per mililiter (ng/mL) | Geometric Coefficient of Variation 15.4 |
| Tepotinib Then Carbamazepine | Maximum Observed Plasma Concentration (Cmax) of Tepotinib | 372 nanogram per mililiter (ng/mL) | Geometric Coefficient of Variation 18.2 |
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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | 31.0 Hours | Geometric Coefficient of Variation 19.4 |
| Tepotinib Then Carbamazepine | Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma | 29.8 Hours | Geometric Coefficient of Variation 25.8 |
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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Apparent Volume of Distribution (Vz/f) for Tepotinib | 801 liters | Geometric Coefficient of Variation 24.3 |
| Tepotinib Then Carbamazepine | Apparent Volume of Distribution (Vz/f) for Tepotinib | 1157 liters | Geometric Coefficient of Variation 21.2 |
Secondary
Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
Number of participants with clinically significant change from baseline in ECG parameters were reported. Clinical Significance was decided by the investigator. 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.
Time frame: Baseline (Day 1) up to 10 Weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| 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
Number of participants with clinically significant change from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. Laboratory investigation included hematology, biochemistry, urinalysis, and coagulation.
Time frame: Baseline (Day 1) up to 10 Weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| 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 |
| Tepotinib | Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values | Coagulation | 0 Participants |
Secondary
Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
Number of participants with clinically significant change from baseline in vital signs. Clinical Significance was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate.
Time frame: Baseline (Day 1) up to 10 Weeks
Population: The safety analysis set included all participants who had received any dose of the study medication.
| 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 10 Weeks
Population: Safety Analysis Set 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 | 17 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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tepotinib | Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | 8.02 Hours |
| Tepotinib Then Carbamazepine | Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib | 8.0 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 60 minutes before tepotinib dosing and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 38, 48, 60, 72, 96, 120, 144, and 168 hours post dose. Predose 60 minutes before carbamazepine dosing and 1, 1.5, 2, 3, 4, 6, and 8 hours post dose
Population: PK analysis set included all participants who had 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. Here 'Overall number of participants analyzed' = overall number of participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Tepotinib | Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | 17.9 liter/hour | Geometric Coefficient of Variation 20.2 |
| Tepotinib Then Carbamazepine | Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib | 26.9 liter/hour | Geometric Coefficient of Variation 14.1 |