Phase I Open-label, Single Dose Study to Investigate the Effect of Hepatic Impairment on the PK of Evobrutinib (M2951)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M2951
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants with normal hepatic function only will be overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion OR
- •Participants with moderately impaired hepatic function only will be considered to have moderately (Child-Pugh class B and confirmed liver cirrhosis) impaired hepatic function and has been clinically stable for at least 1 month prior to Screening OR
- •Participants with mildly impaired hepatic function only will be considered to have mildly (Child-Pugh class A and confirmed liver cirrhosis) impaired hepatic function and has been clinically stable for at least 1 month prior to Screening
- •Have a body weight within 50.0 and 120.0 kilogram (kg) and body mass index (BMI) within the range 19.0 and 36.0 kilogram per square meter (kg/m^2)
- •Female participants are not pregnant or breastfeeding, and at least one of the following conditions applies
- •Not a woman of childbearing potential (WOCBP)
- •Other protocol defined inclusion criteria could apply
排除标准
- •Clinical history of autoimmune disorder with hepatic influence (Hashimoto thyroiditis and rheumatic diseases allowed)
- •History of any malignancy
- •Diseases and surgeries of the gastrointestinal tract, which could influence the gastrointestinal anatomy and mobility. Prior history of cholecystectomy or inflammatory bowel disease, and any clinically relevant surgery within 6 months prior to Screening
- •History of chronic or recurrent acute infection or any bacterial, viral, parasitic or fungal infections within 30 days prior to Screening and at any time between Screening and admission, or hospitalization due to infection within 6 months prior to Screening
- •History of shingles within 12 months prior to Screening
- •History of drug hypersensitivity, ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or formulation ingredients; history of serious allergic reactions leading to hospitalization or any other hypersensitivity reaction in general, which may affect the safety of the participant and/or outcome of the trial per the Investigator's discretion
- •Participants with impaired hepatic function will be excluded who had Primary and secondary biliary cirrhosis.
- •Participants with impaired hepatic function will be excluded with Clinical evidence of severe ascites.
- •Participants with impaired hepatic function will be excluded with Hepatic encephalopathy Grade greater than 1
- •Other protocol defined exclusion criteria could apply
研究组 & 干预措施
Group 1: Normal Hepatic Function (Reference)
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.
干预措施: M2951 (BTK inhibitor) (Drug)
Group 2: Mild Hepatic Impairment
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.
干预措施: M2951 (BTK inhibitor) (Drug)
Group 3: Moderate Hepatic Impairment
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.
干预措施: M2951 (BTK inhibitor) (Drug)
结局指标
主要结局
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M2951
时间窗: 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
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.
Maximum Observed Plasma Concentration (Cmax) of M2951
时间窗: 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
Cmax was obtained directly from the plasma concentration versus time curve.
次要结局
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(up to follow-up (Day 6))
- Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets and Reticulocytes(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(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameter: Hematocrit(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameter: Hemoglobin(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameters: Erythrocytes Mean Corpuscular Volume(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameter: Erythrocytes(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameter: Prothrombin International Normalized Ratio(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Hematology Parameter: Prothrombin Time(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(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Chemistry Parameters: Albumin and Protein(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Urate(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in Chemistry Parameter: C Reactive Protein(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(Baseline, Day 2 and follow-up (Day 6))
- Change From Baseline in 12-lead Electrocardiogram (ECG) Parameter: Heart Rate(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(Baseline, Day 1 and follow-up (Day 6))
- Change From Baseline in Vital Sign Parameters: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Baseline, Day 1, Day 2 and follow-up (Day 6))
- Change From Baseline in Vital Sign Parameter: Pulse Rate(Baseline, Day 1, Day 2 and follow-up (Day 6))
- Change From Baseline in Vital Sign Parameter: Respiratory Rate(Baseline, Day 1, Day 2 and follow-up (Day 6))
- Change From Baseline in Vital Sign Parameter: Temperature(Baseline, Day 1, Day 2 and follow-up (Day 6))
- Time to Reach the Maximum Plasma Concentration (Tmax) of M2951(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(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(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(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(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(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(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(1.5, 4, and 12 hours post-dose)
- Area Under Plasma Concentration for Unbound Drug (M2951) From Time Zero to Infinity (AUC0-inf,u)(1.5, 4, and 12 hours post-dose)
- Maximum Observed Plasma Concentration of Unbound M2951 (Cmax, u)(1.5, 4, and 12 hours post-dose)
- Apparent Oral Clearance (CL,u/F) of Unbound M2951(1.5, 4, and 12 hours post-dose)