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| Name | Class |
|---|---|
| Merck KGaA, Darmstadt, Germany | INDUSTRY |
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The study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics (PK), safety and tolerability of tepotinib.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy Participants (Control) | Experimental | Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. |
|
| Mild Hepatic Impairment (Child-Pugh Class A) | Experimental | Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
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| Moderate Hepatic Impairment (Child-Pugh Class B) | Experimental | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tepotinib | Drug | Participants received a single oral dose of tepotinib in Part 1. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity ( AUC0-inf ) of Tepotinib | The area under the plasma concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) 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 (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time profile. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tepotinib | Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | EMD Serono Research & Development Institute, Inc., the biopharmaceutical division of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Qps Mra, Llc | Miami | Florida | 33143 | United States | ||
| Orlando Clinical Research Center |
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| Label | URL |
|---|---|
| Trial Awareness and Transparency website | View source |
| US Medical Information website, Medical Resources | View source |
| 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) |
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The study was planned to be conducted in 2 parts: Part 1 and Part 2. Part 2 of the study was optional and sponsor decided not to perform part 2 of the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Participants (Control) | Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| FG001 | Mild Hepatic Impairment (Child-Pugh Class A) | Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| FG002 | Moderate Hepatic Impairment (Child-Pugh Class B) | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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The Safety Analysis Set included all participants who received tepotinib.
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Participants (Control) | Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| BG001 | Mild Hepatic Impairment (Child-Pugh Class A) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity ( AUC0-inf ) of Tepotinib | The area under the plasma concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pharmacokinetic (PK) Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanogram*hour per milliliter (ng*h/mL) | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
|
For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Healthy Participants (Control) | Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA Version 21.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Communication Center | Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@emdgroup.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 24, 2018 | Jun 4, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 31, 2018 | Jun 25, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C000707607 | tepotinib |
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| Apparent Terminal Half Life (t1/2) of Tepotinib | Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Apparent Total Body Clearance (CL/f) of Tepotinib | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for tepotinib. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Apparent Volume of Distribution During Terminal Phase (VZ/f) of Tepotinib | Apparent volume of distribution during the terminal phase following extravascular administration for tepotinib was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity as a Percentage of AUC0-Inf (AUCextra) of Tepotinib | AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t/AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity as a Percentage of AUC0-Inf (AUCextra) of Tepotinib Metabolite (MSC2571109) | AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t/AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity as a Percentage of AUC0-Inf (AUCextra) of Tepotinib Metabolite (MSC2571107) | AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t/AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Area Under the Plasma Concentration Time Curve for Unbound Drug From Time Zero (Dosing Time) Extrapolated to Infinity (AUC0-inf, u) of Tepotinib | Area under the concentration-time curve for unbound drug from time zero to infinity, calculated as AUC0-inf_pred multiplied by fu. Fu is the fraction of analyte unbound. Free fraction was calculated as the ratio of free concentration divided by total concentration at a given sampling point. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Maximum Observed Unbound Plasma Concentration (Cmax,u) of Tepotinib | Maximum unbound plasma drug concentration, was calculated as Cmax*fu. Fu is the fraction of analyte unbound. Free fraction was calculated as the ratio of free concentration divided by total concentration at a given sampling point. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Apparent Total Body Clearance of Unbound Drug Following Extravascular Administration (CL/f,u) of Tepotinib | Unbound apparent oral clearance, was calculated as CL/f,u = Dose divided by AUC0-inf_pred/fu. Fu is the fraction of analyte unbound. Free fraction was calculated as the ratio of free concentration divided by total concentration at a given sampling point. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | AUC0-t at which the concentration was at or above lower limit of quantification (LLOQ) was calculated according to the mixed log linear trapezoidal rule. Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | The area under the concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | Cmax was taken directly from the observed concentration-time profile. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Time to Reach Maximum Observation Plasma Concentration (Tmax) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Apparent Terminal Half Life (t1/2) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Metabolite (MSC2571109 or MSC2571107) Area Under Curve From Time Zero Extrapolated To Infinity (AUC0-inf) to Tepotinib (AUC0-inf) Ratio | The area under the concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. Ratio of AUC0-inf of Metabolite (MSC2571109 or MSC2571107) to AUC0-inf of tepotinib was reported. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Metabolite (MSC2571109 or MSC2571107) Maximum Observed Plasma Concentration Observed (Cmax) to Tepotinib Cmax Ratio | Cmax was taken directly from the observed concentration-time profile. Ratio of Cmax of Metabolite (MSC2571109 or MSC2571107) to Cmax of tepotinib was reported. | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs were reported. | For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22 |
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Laboratory assessments included hematology, biochemistry, coagulation and urinalysis. Number of participants with clinically significant changes from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. | For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22 |
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and 12-lead Electrocardiogram (ECG) Findings | Vital signs included body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. Number of participants with clinically significant changes from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator. | For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22 |
| Orlando |
| Florida |
| 32809 |
| United States |
| View source |
Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| BG002 | Moderate Hepatic Impairment (Child-Pugh Class B) | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| BG003 | Total | Total of all reporting groups |
| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| Description |
|---|
| OG000 | Healthy Participants (Control) | Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| OG001 | Mild Hepatic Impairment (Child-Pugh Class A) | Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
| OG002 | Moderate Hepatic Impairment (Child-Pugh Class B) | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. |
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| Primary | Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) 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 (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Primary | Maximum Observed Plasma Concentration (Cmax) of Tepotinib | Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time profile. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanogram per milliliter (ng/mL) | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tepotinib | Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Median | Full Range | Hours | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Apparent Terminal Half Life (t1/2) of Tepotinib | Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Median | Full Range | Hours | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Apparent Total Body Clearance (CL/f) of Tepotinib | Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for tepotinib. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Apparent Volume of Distribution During Terminal Phase (VZ/f) of Tepotinib | Apparent volume of distribution during the terminal phase following extravascular administration for tepotinib was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity as a Percentage of AUC0-Inf (AUCextra) of Tepotinib | AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t/AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. | PK analysis set was used. Summary statistics for this parameter was not reported because it is a diagnostic parameter, rather than a PK parameter in the proper sense. It was only used to assess the individual data, not the group level. Therefore, individual data was reported for this outcome measure. Here, "Number Analyzed"= specific participant evaluated in respective arm. | Posted | Number | Percentage of AUC0-inf | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity as a Percentage of AUC0-Inf (AUCextra) of Tepotinib Metabolite (MSC2571109) | AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t/AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. | PK analysis set was used. Summary statistics for this parameter was not reported because it is a diagnostic parameter, rather than a PK parameter in the proper sense. It was only used to assess the individual data, not the group level. Therefore, individual data was reported for this outcome measure. Here, "Number Analyzed"= specific participant evaluated in respective arm. | Posted | Number | Percentage of AUC0-inf | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity as a Percentage of AUC0-Inf (AUCextra) of Tepotinib Metabolite (MSC2571107) | AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t/AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf. | PK analysis set was used. Summary statistics for this parameter was not reported because it is a diagnostic parameter, rather than a PK parameter in the proper sense. It was only used to assess the individual data, not the group level. Therefore, individual data was reported for this outcome measure. Here, "Number Analyzed"= specific participant evaluated in respective arm. | Posted | Number | Percentage of AUC0-inf | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Area Under the Plasma Concentration Time Curve for Unbound Drug From Time Zero (Dosing Time) Extrapolated to Infinity (AUC0-inf, u) of Tepotinib | Area under the concentration-time curve for unbound drug from time zero to infinity, calculated as AUC0-inf_pred multiplied by fu. Fu is the fraction of analyte unbound. Free fraction was calculated as the ratio of free concentration divided by total concentration at a given sampling point. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Maximum Observed Unbound Plasma Concentration (Cmax,u) of Tepotinib | Maximum unbound plasma drug concentration, was calculated as Cmax*fu. Fu is the fraction of analyte unbound. Free fraction was calculated as the ratio of free concentration divided by total concentration at a given sampling point. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Apparent Total Body Clearance of Unbound Drug Following Extravascular Administration (CL/f,u) of Tepotinib | Unbound apparent oral clearance, was calculated as CL/f,u = Dose divided by AUC0-inf_pred/fu. Fu is the fraction of analyte unbound. Free fraction was calculated as the ratio of free concentration divided by total concentration at a given sampling point. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | AUC0-t at which the concentration was at or above lower limit of quantification (LLOQ) was calculated according to the mixed log linear trapezoidal rule. Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | The area under the concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Maximum Observed Plasma Concentration (Cmax) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | Cmax was taken directly from the observed concentration-time profile. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Time to Reach Maximum Observation Plasma Concentration (Tmax) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Median | Full Range | Hours | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Apparent Terminal Half Life (t1/2) of Tepotinib Metabolites (MSC2571109 and MSC2571107) | Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Median | Full Range | Hours | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Metabolite (MSC2571109 or MSC2571107) Area Under Curve From Time Zero Extrapolated To Infinity (AUC0-inf) to Tepotinib (AUC0-inf) Ratio | The area under the concentration time curve (AUC) from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at the last sampling time (tlast), as estimated using the linear regression from lambda z determination. AUC0-inf = AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve. Ratio of AUC0-inf of Metabolite (MSC2571109 or MSC2571107) to AUC0-inf of tepotinib was reported. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Ratio | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Metabolite (MSC2571109 or MSC2571107) Maximum Observed Plasma Concentration Observed (Cmax) to Tepotinib Cmax Ratio | Cmax was taken directly from the observed concentration-time profile. Ratio of Cmax of Metabolite (MSC2571109 or MSC2571107) to Cmax of tepotinib was reported. | PK Analysis Set included all participants who received a single dose of tepotinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events that could affect the PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | Ratio | Pre-dose and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336 and 504 hours (for hepatic impaired participants only) post-dose on Day 1 |
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| Secondary | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs were reported. | Safety Analysis Set included all participants who received tepotinib. | Posted | Count of Participants | Participants | For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22 |
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| Secondary | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Laboratory assessments included hematology, biochemistry, coagulation and urinalysis. Number of participants with clinically significant changes from baseline in laboratory parameters were reported. Clinical Significance was decided by the investigator. | Safety Analysis Set included all participants who received tepotinib. | Posted | Count of Participants | Participants | For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22 |
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| Secondary | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs and 12-lead Electrocardiogram (ECG) Findings | Vital signs included body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. Number of participants with clinically significant changes from baseline in vital signs and ECG were reported. Clinical Significance was decided by the investigator. | Safety Analysis Set included all participants who received tepotinib. | Posted | Count of Participants | Participants | For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22 |
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| 0 |
| 6 |
| 0 |
| 6 |
| 1 |
| 6 |
| EG001 | Mild Hepatic Impairment (Child-Pugh Class A) | Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. | 0 | 6 | 0 | 6 | 0 | 6 |
| EG002 | Moderate Hepatic Impairment (Child-Pugh Class B) | Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. | 0 | 6 | 0 | 6 | 2 | 6 |
| Ear infection | Infections and infestations | MedDRA Version 21.1 | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA Version 21.1 | Non-systematic Assessment |
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Not provided
| Ratio of Geometric Least Square Mean (%) |
| 87.20 |
| 2-Sided |
| 90 |
| 58.94 |
| 129.00 |
| Other |
| Ratio of Geometric Least Square Mean (%) |
| 71.02 |
| 2-Sided |
| 90 |
| 56.08 |
| 89.93 |
| Other |
| Participant 2 |
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| Participant 3 |
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| Participant 4 |
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| Participant 5 |
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| Participant 6 |
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| Participant 2 |
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| Participant 3 |
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| Participant 4 |
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| Participant 5 |
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| Participant 6 |
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| Participant 2 |
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| Participant 3 |
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| Participant 4 |
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| Participant 5 |
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| Participant 6 |
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| Ratio of Geometric Least Square Mean (%) |
| 136.59 |
| 2-Sided |
| 90 |
| 75.50 |
| 247.12 |
For MSC2571109 |
| Other |
| Ratio of Geometric Least Square Mean (%) | 100.47 | 2-Sided | 90 | 54.53 | 185.10 | For MSC2571107 | Other |
| Ratio of Geometric Least Square Mean (%) | 94.48 | 2-Sided | 90 | 51.28 | 174.07 | For MSC2571107 | Other |
|
| Ratio of Geometric Least Square Mean (%) |
| 137.51 |
| 2-Sided |
| 90 |
| 76.08 |
| 248.54 |
For MSC2571109 |
| Other |
| Ratio of Geometric Least Square Mean (%) | 100.81 | 2-Sided | 90 | 55.16 | 184.23 | For MSC2571107 | Other |
| Ratio of Geometric Least Square Mean (%) | 96.18 | 2-Sided | 90 | 52.63 | 175.78 | For MSC2571107 | Other |
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| Ratio of Geometric Least Square Mean (%) |
| 114.80 |
| 2-Sided |
| 90 |
| 77.76 |
| 169.48 |
For MSC2571109 |
| Other |
| Ratio of Geometric Least Square Mean (%) | 106.51 | 2-Sided | 90 | 70.25 | 161.49 | For MSC2571107 | Other |
| Ratio of Geometric Least Square Mean (%) | 72.58 | 2-Sided | 90 | 47.87 | 110.04 | For MSC2571107 | Other |
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| Title | Measurements |
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