A Phase 1 interventional study of Tepotinib in Hepatic Impairment, sponsored by EMD Serono Research & Development Institute, Inc.. Completed at 2 sites in United States. Open to participants aged 18 Years to 75 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-08-12.
Sponsored by EMD Serono Research & Development Institute, Inc. · Phase 1, Interventional, and Other
The study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics (PK), safety and tolerability of tepotinib.
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This study's enrollment of 18 is below the median of 50 across 1,323 interventional studies indexed under Liver Diseases.
Browse Liver Diseases studies →EMD Serono Research & Development Institute, Inc. is the lead sponsor of 85 studies on the registry; 8 are open to participants now.
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Exclusion Criteria:
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.
Drug: Tepotinib
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.
Drug: Tepotinib
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.
Drug: Tepotinib
Participants received a single oral dose of tepotinib in Part 1.
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.
Time frame: 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).
Time frame: 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.
Time frame: 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 Observed Plasma Concentration (Tmax) of Tepotinib
Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Time frame: 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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22
| Milestone | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Started | 6 | 6 | 6 |
| Completed | 6 | 6 | 6 |
| Not completed | 0 | 0 | 0 |
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.
| Nanogram*hour per milliliter (ng*h/mL) | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity ( AUC0-inf ) of Tepotinib | 27500 ± 13.4 | 26100 ± 63.9 | 24200 ± 26.9 |
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).
| ng*h/mL | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tepotinib | 27000 ± 13.8 | 25600 ± 65.6 | 23500 ± 27.4 |
Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time profile.
| Nanogram per milliliter (ng/mL) | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Tepotinib | 406 ± 12.2 | 416 ± 31.5 | 288 ± 23.5 |
Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
| Hours | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Tepotinib | 11 (10.00 to 12.00) | 11.00 (8.00 to 24.00) | 16.00 (6.00 to 30.08) |
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.
| Hours | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Terminal Half Life (t1/2) of Tepotinib | 36.8 (32.3 to 48.4) | 43.7 (31.3 to 55.2) | 46.1 (41.9 to 74.4) |
Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for tepotinib.
| Liter per hour | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Total Body Clearance (CL/f) of Tepotinib | 16.4 ± 13.4 | 17.2 ± 63.9 | 18.6 ± 26.9 |
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.
| Liter | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Volume of Distribution During Terminal Phase (VZ/f) of Tepotinib | 892 ± 11.4 | 1050 ± 45.3 | 1400 ± 20.4 |
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.
| Percentage of AUC0-inf | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Participant 1 | 1.34 | 5.01 | 3.35 |
| Participant 2 | 1.06 | 0.895 | 3.03 |
| Participant 3 | 2.14 | 1.33 | 1.49 |
| Participant 4 | 1.22 | 1.16 | 1.80 |
| Participant 5 | 2.45 | 1.55 | 1.60 |
| Participant 6 | 2.08 | 1.41 | 3.87 |
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.
| Percentage of AUC0-inf | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Participant 1 | 0.799 | 1.44 | 2.05 |
| Participant 2 | 1.28 | 0.574 | 1.41 |
| Participant 3 | 0.737 | 0.605 | 1.06 |
| Participant 4 | 0.677 | 0.470 | 3.06 |
| Participant 5 | 1.55 | 0.482 | 0.522 |
| Participant 6 | 1.07 | 0.621 | 1.96 |
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.
| Percentage of AUC0-inf | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Participant 1 | 0.592 | 3.69 | 2.10 |
| Participant 2 | 0.925 | 0.848 | 5.68 |
| Participant 3 | 0.671 | 0.516 | 0.683 |
| Participant 4 | 0.639 | 0.513 | 3.08 |
| Participant 5 | 1.77 | 0.731 | 2.45 |
| Participant 6 | 0.904 | 1.15 | 1.97 |
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.
| ng*h/mL | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under the Plasma Concentration Time Curve for Unbound Drug From Time Zero (Dosing Time) Extrapolated to Infinity (AUC0-inf, u) of Tepotinib | 532 ± 26.4 | 585 ± 40.5 | 653 ± 33.3 |
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.
| ng/mL | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Maximum Observed Unbound Plasma Concentration (Cmax,u) of Tepotinib | 7.87 ± 25.6 | 9.32 ± 22.5 | 7.80 ± 22.3 |
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.
| Liter per hour | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Total Body Clearance of Unbound Drug Following Extravascular Administration (CL/f,u) of Tepotinib | 845 ± 26.4 | 770 ± 40.5 | 689 ± 33.3 |
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).
| ng*h/mL | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 13300 ± 29.5 | 11000 ± 74.8 | 18100 ± 80.7 |
| MSC2571107 | 1120 ± 34.1 | 1120 ± 88.8 | 1050 ± 70.4 |
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.
| ng*h/mL | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 13400 ± 29.3 | 11100 ± 74.3 | 18500 ± 80.9 |
| MSC2571107 | 1130 ± 33.7 | 1140 ± 87.2 | 1080 ± 69.2 |
Cmax was taken directly from the observed concentration-time profile.
| ng/mL | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 143 ± 33.9 | 132 ± 47.3 | 165 ± 37.9 |
| MSC2571107 | 13.9 ± 39.2 | 14.8 ± 55.2 | 10.1 ± 32.1 |
Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
| Hours | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 24.00 (24.00 to 48.00) | 24.00 (24.00 to 48.00) | 54.00 (24.00 to 72.00) |
| MSC2571107 | 24.00 (24.00 to 30.00) | 24.00 (24.00 to 24.00) | 30.00 (16.00 to 72.00) |
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.
| Hours | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 46.3 (43.9 to 56.4) | 57.5 (32.9 to 67.5) | 78.8 (55.5 to 128) |
| MSC2571107 | 46.8 (43.8 to 58.6) | 40.7 (33.9 to 69.8) | 75.4 (53.3 to 137) |
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.
| Ratio | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 0.489 ± 31.8 | 0.424 ± 24.7 | 0.764 ± 49.5 |
| MSC2571107 | 0.0410 ± 34.7 | 0.0435 ± 32.3 | 0.0449 ± 40.0 |
Cmax was taken directly from the observed concentration-time profile. Ratio of Cmax of Metabolite (MSC2571109 or MSC2571107) to Cmax of tepotinib was reported.
| Ratio | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| MSC2571109 | 0.353 ± 27.5 | 0.318 ± 30.0 | 0.571 ± 37.3 |
| MSC2571107 | 0.0343 ± 29.2 | 0.0357 ± 32.9 | 0.0351 ± 27.1 |
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.
| Participants | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 1 | 0 | 2 |
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.
| Participants | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 | 0 | 0 |
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.
| Participants | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Vital Signs | 0 | 0 | 0 |
| ECG Findings | 0 | 0 | 0 |
Collected over For Healthy Participants: Day 1 up to Day 15; For Hepatic Impaired Participants: Day 1 up to Day 22. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Healthy Participants (Control) | 0/6 (0%) | 0/6 (0%) | 1/6 (16.7%) |
| Mild Hepatic Impairment (Child-Pugh Class A) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) |
| Moderate Hepatic Impairment (Child-Pugh Class B) | 0/6 (0%) | 0/6 (0%) | 2/6 (33.3%) |
| Event | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| DiarrhoeaGastrointestinal disorders | 1/6 | 0/6 | 0/6 |
| Ear infectionInfections and infestations | 0/6 | 0/6 | 1/6 |
| RashSkin and subcutaneous tissue disorders | 0/6 | 0/6 | 1/6 |
The Safety Analysis Set included all participants who received tepotinib.
| Age, Continuous(Years) | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| Mean | 59 ± 8.0 | 61 ± 3.9 | 60 ± 10.0 | 60 ± 7.3 |
| Sex: Female, Male(Participants) | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| Female | 1 | 2 | 1 | 4 |
| Male | 5 | 4 | 5 | 14 |
| Ethnicity (NIH/OMB)(Participants) | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| Hispanic or Latino | 3 | 1 | 0 | 4 |
| Not Hispanic or Latino | 3 | 5 | 6 | 14 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Healthy Participants (Control) | Mild Hepatic Impairment (Child-Pugh Class A) | Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 2 | 0 | 1 | 3 |
| White | 4 | 5 | 5 | 14 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
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