A Phase 1 interventional study of M2951 (BTK inhibitor) in Hepatic Impairment, sponsored by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany. Completed at 1 site in Germany. Open to participants aged 18 Years to 79 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-10-28.
Sponsored by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany · Phase 1, Interventional, and Treatment
This study was to investigate the pharmacokinetic (PK) and safety of M2951 (Bruton's tyrosine kinase [BTK] inhibitor) in participants with different degrees of hepatic impairment compared to participants with normal hepatic function.
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany is the lead sponsor of 55 studies on the registry; 5 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Participants with normal hepatic function received single oral dose of 30 milligrams (mg) M2951 (3 film-coated tablets of 10 mg) on Day 1 after a standard breakfast.
Drug: M2951 (BTK inhibitor)
Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 30 mg M2951 (3 film-coated tablets of 10 mg) on Day 1 after a standard breakfast. The Child-Pugh Score was a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon serum albumin, ascites, serum bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
Drug: M2951 (BTK inhibitor)
Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 30 mg M2951 (3 film-coated tablets of 10 mg) on Day 1 after a standard breakfast. The Child-Pugh Score was a scoring system used to determine the prognosis with cirrhosis and need for liver transplantation. Scoring is based upon serum albumin, ascites, serum bilirubin, prothrombin time, and encephalopathy. Each category is based on a scoring system of 1-3 with 3 being the worst and a total score range of 5-15. It is broken into categories A (score of 5-6), B (score of 7-9), and C (score of 10-15) with worsening from A to C for prognosis.
Drug: M2951 (BTK inhibitor)
Participants received a single oral dose of M2951 (BTK inhibitor) on Day 1.
Also known as: Evobrutinib
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M2951
AUC0-inf was calculated by combining AUC0-tlast and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Maximum Observed Plasma Concentration (Cmax) of M2951
Cmax was obtained directly from the plasma concentration versus time curve.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any unfavorable 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. TEAEs were defined as events that started or worsened that in severity after at least one dose of the study intervention has been administered. TEAEs included both serious TEAEs and non-serious TEAEs.
Time frame: up to follow-up (Day 6)
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets and Reticulocytes
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameters: basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils, platelets and reticulocytes. Change from baseline in hematology parameters: basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils, platelets, and reticulocytes at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes and Reticulocytes/Erythrocytes
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameters: basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes and reticulocytes/erythrocytes. Change From Baseline in hematology parameters: basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes and reticulocytes/erythrocytes at Day 2 and Day 6 were reported in percentage.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Change from baseline in hematology parameter: erythrocytes mean corpuscular hemoglobin at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameters: Erythrocytes Mean Corpuscular Volume
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: erythrocytes mean corpuscular volume. Change from baseline in hematology parameter: erythrocytes mean corpuscular volume at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameter: Erythrocytes
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameters: erythrocytes. Change from baseline in hematology parameters: erythrocytes at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameter: Hematocrit
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: hematocrit. Change from baseline in hematology parameter: hematocrit at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameter: Hemoglobin
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: hemoglobin. Change from baseline in hematology parameter: hemoglobin at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameter: Prothrombin International Normalized Ratio
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: Prothrombin International Normalized Ratio. International Normalized Ratio (INR) is calculated based on the prothrombin time (PT) test results. The INR is the ratio of a participant's prothrombin time to a normal (control) sample, raised to the power of the International Sensitivity Index (ISI) value for the analytical system being used. Change from baseline in hematology parameter: prothrombin international normalized ratio at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Hematology Parameter: Prothrombin Time
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: prothrombin time. Prothrombin Time measures how long it takes for a clot to form in a blood sample. Change from baseline in hematology parameter: prothrombin time at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Chemistry Parameters: Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Creatine Kinase, Gamma Glutamyl Transferase, Lactate Dehydrogenase, Lipase
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Amylase, Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT), Lactate Dehydrogenase (LDH) and Lipase. Change from baseline in chemistry parameters: ALT, ALP, Amylase, AST, CK, GGT, LDH and Lipase at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Chemistry Parameters: Albumin and Protein
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Albumin and Protein. Change from baseline in chemistry parameters: albumin and protein level at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Urate
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Bilirubin, Creatinine and Urate. Change from baseline in chemistry parameters: bilirubin, creatinine and urate level at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Chemistry Parameter: C Reactive Protein
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameter: C Reactive Protein. Change from baseline in chemistry parameters: C Reactive Protein level at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in Chemistry Parameters: Calcium, Chloride, Cholesterol, Glucose, Magnesium, Phosphate, Potassium, Sodium, Triglycerides, Urea and Urea Nitrogen
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Calcium, Chloride, Cholesterol, Glucose, Magnesium, Phosphate, Potassium, Sodium, Triglycerides, Urea and Urea Nitrogen. Change from baseline in chemistry parameters: Calcium, Chloride, Cholesterol, Glucose, Magnesium, Phosphate, Potassium, Sodium, Triglycerides, Urea and Urea Nitrogen level at Day 2 and Day 6 were reported.
Time frame: Baseline, Day 2 and follow-up (Day 6)
Change From Baseline in 12-lead Electrocardiogram (ECG) Parameter: Heart Rate
12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in supine position by using an ECG machine that automatically calculates the heart rate. Change from baseline in 12-lead ECG parameter: heart rate at Day 1 and Day 6 were reported.
Time frame: Baseline, Day 1 and follow-up (Day 6)
Change From Baseline in 12-lead Electrocardiogram (ECG) Parameters: PQ/PR Interval, QRS Duration, QT Interval, Corrected QT Interval Using Fridericia's Formula (QTcF) and RR Duration at Day 1 and Day 6
12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in supine position by using an ECG machine that automatically measures PQ/PR, QRS, QT, and QTc intervals and RR duration. Change From Baseline in 12-ECG parameters: PQ/PR interval, QRS duration, QT interval, QTcF interval and RR duration at Day 1 and Day 6 were reported.
Time frame: Baseline, Day 1 and follow-up (Day 6)
Change From Baseline in Vital Sign Parameters: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
SBP and DBP were measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in SBP and DBP at Days 1, 2 and 6 were reported.
Time frame: Baseline, Day 1, Day 2 and follow-up (Day 6)
Change From Baseline in Vital Sign Parameter: Pulse Rate
Pulse rate was measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Change from baseline in vital sign parameter: pulse rate at Days 1, 2 and 6 were reported.
Time frame: Baseline, Day 1, Day 2 and follow-up (Day 6)
Change From Baseline in Vital Sign Parameter: Respiratory Rate
Respiratory rate was measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Change from baseline in vital sign parameter: respiratory rate at Days 1, 2 and 6 were reported.
Time frame: Baseline, Day 1, Day 2 and follow-up (Day 6)
Change From Baseline in Vital Sign Parameter: Temperature
Temperature was measured in the semi-supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Change from baseline in vital sign parameter: temperature at Days 1, 2 and 6 were reported.
Time frame: Baseline, Day 1, Day 2 and follow-up (Day 6)
Time to Reach the Maximum Plasma Concentration (Tmax) of M2951
Tmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Apparent Elimination Half Life (t1/2) of M2951
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Area Under The Plasma Concentration-Time Curve From Time Zero to Time 12 Hours (AUC0-12) of M2951
AUC0-12 of M2951 was defined as the area under the plasma concentration time curve from time 0 to 12 hours post-dose.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 12.0 hours post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to Time 24 Hours (AUC0-24) of M2951
AUC0-24 of M2951 was defined as the area under the plasma concentration time curve from time 0 to 24 hours post-dose.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0 and 24.0 hours post-dose
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-tlast) of M2951
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-tlast was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Apparent Total Body Clearance (CL/f) of M2951
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLOQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Apparent Volume of Distribution During Terminal Phase (VZ/f) of M2951
Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. AUC0-inf was calculated by combining AUC0-tlast and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0 and 32.0 hours post-dose
Fraction of Unbound Drug (fu) of M2951
fu is defined as the ratio of unbound drug concentration to the total drug concentration.
Time frame: 1.5, 4, and 12 hours post-dose
Area Under Plasma Concentration for Unbound Drug (M2951) From Time Zero to Infinity (AUC0-inf,u)
AUC0-inf,u was calculated as fu \* AUC0-inf. fu was defined as the ratio of unbound drug concentration to the total drug concentration. AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: 1.5, 4, and 12 hours post-dose
Maximum Observed Plasma Concentration of Unbound M2951 (Cmax, u)
Cmax,u was calculated as fu \* Cmax. fu was defined as the ratio of unbound drug concentration to the total drug concentration. Cmax was obtained directly from the concentration versus time curve.
Time frame: 1.5, 4, and 12 hours post-dose
Apparent Oral Clearance (CL,u/F) of Unbound M2951
CL,u/F was calculated as Dose divided by AUC0-inf, u. AUC0-inf,u was calculated as fu \* AUC0-inf. fu was defined as the ratio of unbound drug concentration to the total drug concentration. AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: 1.5, 4, and 12 hours post-dose
| Milestone | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Started | 8 | 8 | 8 |
| Completed | 8 | 8 | 8 |
| Not completed | 0 | 0 | 0 |
AUC0-inf was calculated by combining AUC0-tlast and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
| hour*nanogram per milliliter (h*ng/mL) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M2951 | 186 ± 23.6 | 232 ± 60.6 | 362 ± 21.8 |
Cmax was obtained directly from the plasma concentration versus time curve.
| nanogram per milliliter (ng/mL) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of M2951 | 63.8 ± 14.2 | 79.2 ± 86.2 | 118 ± 29.9 |
An adverse event (AE) was defined as any unfavorable 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. TEAEs were defined as events that started or worsened that in severity after at least one dose of the study intervention has been administered. TEAEs included both serious TEAEs and non-serious TEAEs.
| Participants | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 0 | 0 | 1 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameters: basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils, platelets and reticulocytes. Change from baseline in hematology parameters: basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils, platelets, and reticulocytes at Day 2 and Day 6 were reported.
| 10^9 cells per liter | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Basophils: Day 2 | -0.006 ± 0.0160 | -0.005 ± 0.0107 | -0.003 ± 0.0175 |
| Basophils: follow- up (Day 6) | -0.003 ± 0.0128 | 0.004 ± 0.0119 | 0.006 ± 0.0119 |
| Eosinophils: Day 2 | -0.007 ± 0.0984 | -0.025 ± 0.0568 | 0.010 ± 0.0650 |
| Eosinophils: follow- up (Day 6) | 0.000 ± 0.0626 | -0.040 ± 0.0518 | 0.016 ± 0.1051 |
| Leukocytes: Day 2 | 0.54 ± 0.597 | -0.28 ± 0.504 | -0.68 ± 1.074 |
| Leukocytes: follow- up (Day 6) | 0.11 ± 0.751 | -0.10 ± 0.857 | -0.66 ± 1.265 |
| Lymphocytes: Day 2 | 0.233 ± 0.3186 | -0.055 ± 0.1099 | 0.141 ± 0.3541 |
| Lymphocytes: follow- up (Day 6) | 0.146 ± 0.3074 | 0.046 ± 0.1994 | 0.024 ± 0.2900 |
| Monocytes: Day 2 | 0.004 ± 0.0752 | 0.009 ± 0.0930 | -0.076 ± 0.1905 |
| Monocytes: follow- up (Day 6) | 0.008 ± 0.0761 | 0.071 ± 0.1173 | -0.033 ± 0.1618 |
| Neutrophils: Day 2 | 0.300 ± 0.4459 | -0.186 ± 0.4348 | -0.744 ± 0.9999 |
| Neutrophils: follow- up (Day 6) | -0.043 ± 0.8141 | -0.169 ± 0.7111 | -0.659 ± 1.1235 |
| Platelets: Day 2 | -3.3 ± 21.12 | -16.5 ± 13.72 | -27.3 ± 18.73 |
| Platelets: follow- up (Day 6) | -7.0 ± 21.85 | -12.0 ± 9.80 | -22.3 ± 23.89 |
| Reticulocytes: Day 2 | 3.50 ± 5.025 | -1.97 ± 9.358 | -5.01 ± 7.052 |
| Reticulocytes: follow- up (Day 6) | 2.51 ± 7.248 | -3.14 ± 4.541 | 4.76 ± 10.136 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameters: basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes and reticulocytes/erythrocytes. Change From Baseline in hematology parameters: basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes and reticulocytes/erythrocytes at Day 2 and Day 6 were reported in percentage.
| percentage of cells | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Basophils/Leukocytes: Day 2 | -0.16 ± 0.185 | -0.04 ± 0.207 | 0.01 ± 0.323 |
| Basophils/Leukocytes: follow- up (Day 6) | -0.08 ± 0.212 | 0.06 ± 0.283 | 0.21 ± 0.348 |
| Eosinophils/Leukocytes: Day 2 | -0.33 ± 1.285 | -0.29 ± 0.933 | 0.31 ± 1.249 |
| Eosinophils/Leukocytes: follow- up (Day 6) | -0.04 ± 0.924 | -0.45 ± 0.802 | 0.50 ± 1.379 |
| Lymphocytes/Leukocytes: Day 2 | 0.95 ± 3.575 | -0.18 ± 1.689 | 3.66 ± 6.029 |
| Lymphocytes/Leukocytes: follow- up (Day 6) | 1.49 ± 6.414 | 1.25 ± 2.968 | 2.26 ± 4.562 |
| Monocytes/Leukocytes: Day 2 | -0.59 ± 1.034 | 0.39 ± 1.578 | 0.04 ± 1.550 |
| Monocytes/Leukocytes: follow- up (Day 6) | -0.11 ± 0.989 | 1.33 ± 1.433 | 0.56 ± 2.042 |
| Neutrophils/Leukocytes: Day 2 | 0.12 ± 4.556 | 0.11 ± 3.328 | -4.02 ± 6.968 |
| Neutrophils/Leukocytes: follow- up (Day 6) | -1.26 ± 7.166 | -2.19 ± 4.008 | -3.54 ± 7.499 |
| Reticulocytes/Erythrocyte: Day 2 | 0.076 ± 0.1131 | 0.008 ± 0.1978 | -0.083 ± 0.1581 |
| Reticulocytes/Erythrocyte: follow- up (Day 6) | 0.085 ± 0.1640 | 0.006 ± 0.1314 | 0.210 ± 0.3447 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Change from baseline in hematology parameter: erythrocytes mean corpuscular hemoglobin at Day 2 and Day 6 were reported.
| picogram | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | -0.04 ± 0.307 | -0.25 ± 0.389 | -0.07 ± 0.373 |
| Follow- up (Day 6) | -0.09 ± 0.348 | -0.02 ± 0.225 | 0.06 ± 0.487 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: erythrocytes mean corpuscular volume. Change from baseline in hematology parameter: erythrocytes mean corpuscular volume at Day 2 and Day 6 were reported.
| femtoliters | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | 0.14 ± 0.983 | 0.03 ± 1.562 | -0.22 ± 1.445 |
| Follow- up (Day 6) | 0.61 ± 0.969 | 0.54 ± 0.940 | -0.19 ± 0.662 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameters: erythrocytes. Change from baseline in hematology parameters: erythrocytes at Day 2 and Day 6 were reported.
| 10^12 cells per liter | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | 0.017 ± 0.1945 | -0.096 ± 0.2894 | -0.113 ± 0.2858 |
| Follow- up (Day 6) | -0.083 ± 0.1348 | -0.163 ± 0.1992 | -0.179 ± 0.1787 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: hematocrit. Change from baseline in hematology parameter: hematocrit at Day 2 and Day 6 were reported.
| liter of cells per liter of blood (L/L) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | 0.0022 ± 0.01795 | -0.0096 ± 0.02650 | -0.0112 ± 0.03179 |
| Follow- up (Day 6) | -0.0042 ± 0.01059 | -0.0131 ± 0.01840 | -0.0174 ± 0.01683 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: hemoglobin. Change from baseline in hematology parameter: hemoglobin at Day 2 and Day 6 were reported.
| gram per liter (g/L) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | 0.4 ± 5.55 | -4.5 ± 10.43 | -3.6 ± 9.23 |
| Follow- up (Day 6) | -2.9 ± 3.94 | -5.6 ± 6.82 | -5.4 ± 4.44 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: Prothrombin International Normalized Ratio. International Normalized Ratio (INR) is calculated based on the prothrombin time (PT) test results. The INR is the ratio of a participant's prothrombin time to a normal (control) sample, raised to the power of the International Sensitivity Index (ISI) value for the analytical system being used. Change from baseline in hematology parameter: prothrombin international normalized ratio at Day 2 and Day 6 were reported.
| ratio | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | -0.006 ± 0.0160 | 0.006 ± 0.0262 | 0.006 ± 0.0421 |
| Follow- up (Day 6) | 0.021 ± 0.0295 | -0.006 ± 0.0580 | -0.029 ± 0.0391 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the hematology parameter: prothrombin time. Prothrombin Time measures how long it takes for a clot to form in a blood sample. Change from baseline in hematology parameter: prothrombin time at Day 2 and Day 6 were reported.
| seconds | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | -0.12 ± 0.183 | 0.04 ± 0.245 | 0.14 ± 0.396 |
| Follow- up (Day 6) | 0.12 ± 0.337 | -0.06 ± 0.510 | -0.19 ± 0.336 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Amylase, Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT), Lactate Dehydrogenase (LDH) and Lipase. Change from baseline in chemistry parameters: ALT, ALP, Amylase, AST, CK, GGT, LDH and Lipase at Day 2 and Day 6 were reported.
| units per litre (U/L) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| ALT: Day 2 | 0.9 ± 2.23 | -9.4 ± 17.00 | -2.0 ± 3.82 |
| ALT: follow- up (Day 6) | 0.8 ± 2.12 | -7.0 ± 20.50 | -0.4 ± 2.13 |
| ALP: Day 2 | -3.3 ± 5.47 | -14.6 ± 16.04 | -16.1 ± 13.17 |
| ALP: follow- up (Day 6) | 0.4 ± 5.66 | -9.5 ± 14.06 | -9.5 ± 19.27 |
| Amylase: Day 2 | 1.8 ± 15.71 | -11.0 ± 8.32 | 34.1 ± 107.34 |
| Amylase: follow- up (Day 6) | -4.1 ± 6.47 | -2.6 ± 3.46 | 14.1 ± 21.56 |
| AST: Day 2 | -0.5 ± 2.88 | -24.1 ± 51.88 | 2.1 ± 7.38 |
| AST: follow- up (Day 6) | 0.6 ± 1.92 | -15.5 ± 51.39 | 0.8 ± 5.01 |
| CK: Day 2 | -41.9 ± 40.65 | -68.0 ± 27.44 | -36.4 ± 23.08 |
| CK: follow- up (Day 6) | -20.9 ± 44.97 | -15.4 ± 26.42 | -9.5 ± 43.36 |
| GGT: Day 2 | -0.8 ± 1.39 | -22.4 ± 34.98 | 6.5 ± 52.11 |
| GGT: follow- up (Day 6) | -1.0 ± 1.85 | -24.8 ± 43.48 | -27.6 ± 43.00 |
| LDH: Day 2 | -17.6 ± 17.44 | -42.5 ± 35.62 | -11.3 ± 33.72 |
| LDH: follow- up (Day 6) | -13.9 ± 10.44 | -20.9 ± 23.73 | -10.8 ± 12.71 |
| Lipase: Day 2 | 18.4 ± 50.86 | -4.8 ± 3.62 | -16.8 ± 63.92 |
| Lipase: follow- up (Day 6) | -2.4 ± 7.05 | -1.5 ± 5.35 | 10.4 ± 28.61 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Albumin and Protein. Change from baseline in chemistry parameters: albumin and protein level at Day 2 and Day 6 were reported.
| g/L | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Albumin: Day 2 | -1.1 ± 2.64 | -4.0 ± 3.74 | -2.3 ± 3.11 |
| Albumin: follow- up (Day 6) | -0.6 ± 2.00 | -1.5 ± 2.73 | -0.8 ± 0.89 |
| Protein: Day 2 | -1.3 ± 3.11 | -6.0 ± 5.98 | -3.3 ± 4.86 |
| Protein: follow- up (Day 6) | -1.0 ± 2.88 | -2.8 ± 4.92 | -1.5 ± 1.93 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Bilirubin, Creatinine and Urate. Change from baseline in chemistry parameters: bilirubin, creatinine and urate level at Day 2 and Day 6 were reported.
| micromole per liter (mcmol/L) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Bilirubin: Day 2 | -0.42760 ± 1.516108 | 3.41455 ± 7.539097 | 3.20700 ± 7.993130 |
| Bilirubin: follow- up (Day 6) | 0.21380 ± 2.131883 | -0.21380 ± 5.593931 | -2.77940 ± 6.060122 |
| Creatinine: Day 2 | -7.0720 ± 5.21913 | -3.0940 ± 5.88280 | -5.3040 ± 5.78714 |
| Creatinine: follow- up (Day 6) | -0.0000 ± 4.84187 | 1.7680 ± 4.77220 | -0.4420 ± 2.87421 |
| Urate: Day 2 | -25.2790 ± 28.03413 | -24.5355 ± 35.89100 | -15.6135 ± 28.06792 |
| Urate: follow- up (Day 6) | 5.9480 ± 38.80879 | -11.8960 ± 25.82908 | 8.9220 ± 18.80923 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameter: C Reactive Protein. Change from baseline in chemistry parameters: C Reactive Protein level at Day 2 and Day 6 were reported.
| milligram per liter (mg/L) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 2 | -0.04 ± 0.460 | -0.22 ± 0.669 | 0.40 ± 1.593 |
| Follow- up (Day 6) | -0.05 ± 0.404 | 0.26 ± 0.798 | 1.25 ± 2.330 |
Blood samples were collected in a fasted condition (after a fast of at least 8 hours) to analyze the chemistry parameters: Calcium, Chloride, Cholesterol, Glucose, Magnesium, Phosphate, Potassium, Sodium, Triglycerides, Urea and Urea Nitrogen. Change from baseline in chemistry parameters: Calcium, Chloride, Cholesterol, Glucose, Magnesium, Phosphate, Potassium, Sodium, Triglycerides, Urea and Urea Nitrogen level at Day 2 and Day 6 were reported.
| millimole per liter (mmol/L) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Calcium: Day 2 | -0.030 ± 0.0481 | -0.020 ± 0.0878 | -0.036 ± 0.0540 |
| Calcium: follow- up (Day 6) | -0.039 ± 0.0506 | -0.033 ± 0.1074 | -0.090 ± 0.1158 |
| Chloride: Day 2 | 1.0 ± 1.07 | 0.5 ± 2.27 | 2.4 ± 0.92 |
| Chloride: follow- up (Day 6) | -1.6 ± 2.07 | -0.4 ± 1.60 | 1.6 ± 2.62 |
| Cholesterol: Day 2 | 0.03885 ± 0.287412 | -0.26871 ± 0.539200 | -0.18778 ± 0.233203 |
| Cholesterol: follow- up (Day 6) | -0.27519 ± 0.477560 | -0.38203 ± 0.701523 | -0.21691 ± 0.274776 |
| Glucose: Day 2 | 0.09019 ± 0.622942 | 0.05550 ± 1.760321 | -1.94944 ± 2.490078 |
| Glucose: follow- up (Day 6) | 0.17344 ± 0.379258 | -0.32606 ± 0.340109 | -1.87313 ± 3.549490 |
| Magnesium: Day 2 | -0.009 ± 0.0285 | -0.052 ± 0.0742 | -0.001 ± 0.0732 |
| Magnesium: follow- up (Day 6) | -0.014 ± 0.0297 | 0.005 ± 0.0457 | -0.006 ± 0.0758 |
| Phosphate: Day 2 | 0.003 ± 0.0509 | 0.080 ± 0.0953 | 0.105 ± 0.1872 |
| Phosphate: follow- up (Day 6) | -0.005 ± 0.0682 | -0.064 ± 0.1421 | -0.106 ± 0.1897 |
| Potassium: Day 2 | -0.11 ± 0.356 | -0.12 ± 0.266 | -0.34 ± 0.487 |
| Potassium: follow- up (Day 6) | -0.01 ± 0.181 | 0.16 ± 0.396 | -0.38 ± 0.727 |
| Sodium: Day 2 | 0.0 ± 1.60 | -2.8 ± 1.39 | -0.1 ± 2.36 |
| Sodium: follow- up (Day 6) | -0.6 ± 1.77 | -0.9 ± 1.25 | 1.8 ± 2.76 |
| Triglycerides: Day 2 | -0.15538 ± 0.940507 | 0.06356 ± 0.222415 | -0.44776 ± 1.268752 |
| Triglycerides: follow- up (Day 6) | -0.23165 ± 0.875919 | -0.02260 ± 0.326110 | -0.40539 ± 0.781335 |
| Urea: Day 2 | -0.021 ± 0.9152 | 0.531 ± 0.7122 | 0.765 ± 0.8025 |
| Urea: follow- up (Day 6) | -0.213 ± 1.0149 | 0.149 ± 0.5849 | 0.340 ± 0.2570 |
| Urea Nitrogen: Day 2 | 0.0000 ± 0.89505 | 0.5801 ± 0.71240 | 0.7586 ± 0.77366 |
| Urea Nitrogen: follow- up (Day 6) | -0.2231 ± 0.99041 | 0.1785 ± 0.57247 | 0.3570 ± 0.26987 |
12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in supine position by using an ECG machine that automatically calculates the heart rate. Change from baseline in 12-lead ECG parameter: heart rate at Day 1 and Day 6 were reported.
| beats per minute | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 1 | 0.3 ± 5.18 | -0.9 ± 5.33 | 0.9 ± 2.70 |
| Follow- up (Day 6) | 11.8 ± 11.02 | 7.4 ± 11.34 | 5.8 ± 6.34 |
12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in supine position by using an ECG machine that automatically measures PQ/PR, QRS, QT, and QTc intervals and RR duration. Change From Baseline in 12-ECG parameters: PQ/PR interval, QRS duration, QT interval, QTcF interval and RR duration at Day 1 and Day 6 were reported.
| milliseconds | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| PQ/PR Duration: Day 1 | -0.3 ± 4.71 | 0.3 ± 4.46 | -2.0 ± 17.47 |
| PQ/PR Duration: follow-up (Day 6) | -12.5 ± 11.05 | -4.5 ± 9.78 | -10.0 ± 13.52 |
| QRS Duration :Day 1 | 0.0 ± 3.21 | 2.3 ± 5.06 | 6.5 ± 9.06 |
| QRS Duration: follow-up (Day 6) | -1.3 ± 3.01 | 3.0 ± 8.28 | -2.0 ± 7.63 |
| QT Duration: Day 1 | -7.3 ± 17.33 | -0.3 ± 11.97 | -0.5 ± 12.99 |
| QT Duration: follow-up (Day 6) | -24.3 ± 18.77 | -5.5 ± 22.72 | -7.0 ± 20.45 |
| QTcF - Fridericia's Correction Formula: Day 1 | -6.8 ± 20.11 | -1.8 ± 4.89 | 1.5 ± 11.76 |
| QTcF - Fridericia's Correction Formula: follow-up (Day 6) | -2.4 ± 9.98 | 9.1 ± 11.49 | 2.9 ± 15.61 |
| RR Duration: Day 1 | -6.1 ± 79.08 | 9.0 ± 92.82 | -11.0 ± 37.85 |
| RR Duration: follow-up (Day 6) | -148.1 ± 126.54 | -87.4 ± 130.73 | -67.4 ± 91.17 |
SBP and DBP were measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in SBP and DBP at Days 1, 2 and 6 were reported.
| millimeters of mercury (mmHg) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| SBP: Day 1 | 3.5 ± 12.95 | -3.6 ± 3.58 | 2.0 ± 6.70 |
| SBP: Day 2 | 5.6 ± 6.97 | 4.8 ± 13.05 | -1.1 ± 8.68 |
| SBP: follow-up (Day 6) | 0.1 ± 15.58 | 4.8 ± 5.99 | 0.9 ± 13.21 |
| DBP: Day 1 | 1.4 ± 6.86 | -3.5 ± 7.17 | -2.0 ± 4.34 |
| DBP: Day 2 | 1.9 ± 4.58 | 0.6 ± 5.07 | -1.9 ± 4.52 |
| DBP: follow-up (Day 6) | 1.0 ± 7.37 | 3.3 ± 4.74 | 0.5 ± 7.73 |
Pulse rate was measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Change from baseline in vital sign parameter: pulse rate at Days 1, 2 and 6 were reported.
| beats per minute | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 1 | 1.1 ± 2.42 | 1.5 ± 8.26 | -1.4 ± 5.53 |
| Day 2 | 11.3 ± 5.18 | 7.4 ± 7.78 | 8.8 ± 5.34 |
| Follow-up (Day 6) | 11.0 ± 8.07 | 3.6 ± 7.31 | 5.9 ± 6.17 |
Respiratory rate was measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Change from baseline in vital sign parameter: respiratory rate at Days 1, 2 and 6 were reported.
| breaths per minute | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 1 | -1.0 ± 1.69 | 0.9 ± 1.64 | -0.6 ± 1.30 |
| Day 2 | 1.5 ± 2.33 | 0.0 ± 1.51 | -0.8 ± 2.43 |
| Follow-up (Day 6) | 1.0 ± 3.02 | -0.5 ± 0.93 | -0.1 ± 1.46 |
Temperature was measured in the semi-supine position after at least 5 minutes of rest for the participant in a quiet setting without distractions. Change from baseline in vital sign parameter: temperature at Days 1, 2 and 6 were reported.
| degree celsius | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Day 1 | -0.04 ± 0.366 | -0.00 ± 0.438 | -0.01 ± 0.270 |
| Day 2 | 0.46 ± 0.463 | 0.05 ± 0.396 | 0.19 ± 0.348 |
| Follow-up (Day 6) | 0.21 ± 0.223 | 0.14 ± 0.444 | 0.16 ± 0.354 |
Tmax was obtained directly from the concentration versus time curve.
| hours | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Time to Reach the Maximum Plasma Concentration (Tmax) of M2951 | 2.00 (1.00 to 4.00) | 1.76 (0.500 to 3.02) | 1.75 (1.00 to 3.00) |
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
| hours | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Elimination Half Life (t1/2) of M2951 | 1.54 (1.02 to 1.67) | 2.55 (1.55 to 6.56) | 2.65 (1.81 to 3.02) |
AUC0-12 of M2951 was defined as the area under the plasma concentration time curve from time 0 to 12 hours post-dose.
| h*ng/mL | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under The Plasma Concentration-Time Curve From Time Zero to Time 12 Hours (AUC0-12) of M2951 | 184 ± 23.6 | 224 ± 59.7 | 351 ± 21.7 |
AUC0-24 of M2951 was defined as the area under the plasma concentration time curve from time 0 to 24 hours post-dose.
| h*ng/mL | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time 24 Hours (AUC0-24) of M2951 | 185 ± 23.8 | 231 ± 60.1 | 360 ± 22.0 |
Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-tlast was calculated according to the mixed log-linear trapezoidal rule.
| h*ng/mL | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: 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-tlast) of M2951 | 184 ± 23.9 | 228 ± 60.9 | 357 ± 22.3 |
CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLOQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.
| liter per hour (L/h) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Total Body Clearance (CL/f) of M2951 | 162 ± 23.6 | 129 ± 60.6 | 82.9 ± 21.8 |
Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. AUC0-inf was calculated by combining AUC0-tlast and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
| liters | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Volume of Distribution During Terminal Phase (VZ/f) of M2951 | 337 ± 15.2 | 498 ± 53.4 | 301 ± 27.0 |
fu is defined as the ratio of unbound drug concentration to the total drug concentration.
| ratio of unbound drug | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Fraction of Unbound Drug (fu) of M2951 | 5.00 ± 15.3 | 5.78 ± 17.9 | 6.55 ± 11.9 |
AUC0-inf,u was calculated as fu \* AUC0-inf. fu was defined as the ratio of unbound drug concentration to the total drug concentration. AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
| h*ng/mL | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Area Under Plasma Concentration for Unbound Drug (M2951) From Time Zero to Infinity (AUC0-inf,u) | 9.28 ± 30.3 | 13.4 ± 71.7 | 23.7 ± 28.5 |
Cmax,u was calculated as fu \* Cmax. fu was defined as the ratio of unbound drug concentration to the total drug concentration. Cmax was obtained directly from the concentration versus time curve.
| ng/mL | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Maximum Observed Plasma Concentration of Unbound M2951 (Cmax, u) | 3.19 ± 22.8 | 4.57 ± 92.6 | 7.72 ± 36.1 |
CL,u/F was calculated as Dose divided by AUC0-inf, u. AUC0-inf,u was calculated as fu \* AUC0-inf. fu was defined as the ratio of unbound drug concentration to the total drug concentration. AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
| L/h | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Apparent Oral Clearance (CL,u/F) of Unbound M2951 | 3230 ± 30.3 | 2240 ± 71.7 | 1270 ± 28.5 |
Collected over up to follow-up (Day 6). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Group 1: Normal Hepatic Function (Reference) | 0/8 (0%) | 0/8 (0%) | 0/8 (0%) |
| Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | 0/8 (0%) | 0/8 (0%) | 0/8 (0%) |
| Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) | 0/8 (0%) | 0/8 (0%) | 1/8 (12.5%) |
| Event | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) |
|---|---|---|---|
| Back painMusculoskeletal and connective tissue disorders | 0/8 | 0/8 | 1/8 |
The Safety analysis population (SAF) included all participants who were administered any dose of any study intervention.
| Age, Continuous(years) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| Mean | 65.3 ± 5.70 | 58.4 ± 11.30 | 58.9 ± 10.40 | 60.8 ± 9.60 |
| Sex: Female, Male(Participants) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| Female | 3 | 4 | 4 | 11 |
| Male | 5 | 4 | 4 | 13 |
| Ethnicity (NIH/OMB)(Participants) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 2 | 2 |
| Not Hispanic or Latino | 8 | 8 | 6 | 22 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Group 1: Normal Hepatic Function (Reference) | Group 2: Mild Hepatic Impairment (Child-Pugh Class A) | Group 3: Moderate Hepatic Impairment (Child-Pugh Class B) | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 8 | 8 | 8 | 24 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
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Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany