A Phase I, Multicenter, Open-label, Single-dose Study to Assess the Pharmacokinetics of MEK162 in Subjects With Mild, Moderate and Severe Hepatic Impairment
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 27
- 试验地点
- 5
- 主要终点
- PK parameters assessed by Tmax
研究概览
简要总结
This study is a phase I, multi-center, open-label, single oral dose, parallel group study to assess the PK and safety of MEK162 in subjects with impaired hepatic function and healthy subjects with normal hepatic function. Subjects will be assigned by hepatic function defined by elevation of serum total bilirubin and serum AST as determined at the screening and baseline visits. The study population will be healthy male and postmenopausal or sterile female subjects who meet all of the inclusion and none of the exclusion criteria. A minimum of 24 evaluable subjects (6 subjects per group) will be enrolled. The groups are: Group 1-healthy volunteers, Group 2-Mild hepatic impairment, Group 3-Moderate hepatic impairment and Group 4-Severe hepatic impairment. Once approved for enrollment, participants will be confined to the facility for 5 days, given a single dose of MEK162 and monitored for safety assessments, labs and PK will be assessed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Written informed consent prior to any screening procedures
- •Male or female (postmenopausal or sterilized)
- •Subject body weight at least 45 kg and a body mass index (BMI) in the range of 18 to 35.0 kg/m2
- •Subjects with normal hepatic function must have total bilirubin ≤ upper limit of normal (≤ ULN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) ≤ ULN, serum creatinine ≤ ULN, serum amylase and lipase ≤ ULN
- •Additional inclusion criteria for subjects with abnormal liver function determined by elevation of serum total bilirubin are:
- •Absolute neutrophil count (ANC) > 1000 cell/mm3
- •Hb > 9 mg/dl,
- •Platelet count > 30,000/mm3
- •Serum creatinine ≤ 1.8 mg/dl
- •Otherwise considered healthy and free of significant medical disorders unrelated to the subject's hepatic disorder
排除标准
- •Women of child-bearing potential
- •Pregnant or nursing (lactating) women
- •Subjects with impaired cardiovascular function or clinically significant cardiovascular diseases
- •Uncontrolled arterial hypertension despite medical treatment
- •History or current evidence of retinal vein occlusion (RVO) or current risk factors of RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes),
- •History of Gilbert's syndrome
- •Immuno-compromised subjects (including known history/seropositivity of HIV)
- •Any surgical or medical condition (other than hepatic impairment) or receiving any pharmacological treatment which might significantly alter the absorption or metabolism of drugs or which may jeopardize the subject in case of participation in the study
- •Antecedent of malignancy with the following exceptions: adequately treated basal cell or squamous cell carcinoma of the skin
- •Subjects who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
- •Subjects who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
- •History of clinically significant drug allergy
- •Prior therapy with a MEK-inhibitor
- •Use of an investigational drug within 30 days of screening
- •Current smoker or has used tobacco products or products containing nicotine within 7 days prior to dosing of study drug
- •Consumption of alcohol within 3 days prior to dosing or during the study
- •Additional exclusion criteria for subjects with normal hepatic function:
- •Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as ALT, AST, GGT, alkaline phosphatase, or serum bilirubin. ALT and AST beyond the normal range before inclusion Presence of impaired renal function as indicated by abnormal creatinine (creatinine clearance < 80 mL/min) values and/or serum creatinine ≥1.8 mg/dL- A positive Hepatitis B or Hepatitis C test result
- •Additional exclusion criteria for subjects with elevation of serum bilirubin > UNL:
- •Symptoms or history of encephalopathy (Grade II or worse) within 4 weeks of study entry
- •Clinical evidence of severe ascites requiring intervention
- •International normalized ratio (INR) >2.5
- •Any evidence of progressive liver disease within the last 3 weeks prior to the screening visit) as indicated by worsening of clinical manifestations (i.e.: ascites, encephalopathy) and/or laboratories abnormalities (liver transaminases, alkaline phosphatase and GGT or a ≥ 50% worsening of serum bilirubin or prothrombin time)
- •History of surgical portosystemic shunt with complications (i.e. hepatic encephalopathy, heart failure)
- •Active bleeding during the last 28 days prior to dosing including variceal bleeding
研究组 & 干预措施
MEK162
A minimum of 24 subjects (6 subjects per group) will be enrolled. Enrollment into Group 1 (control group with normal hepatic function) should be similar to the enrollment into Group 2, 3 and 4 with respect to age, gender, and body weight. Enrollment into Group 1 will remain open until the enrollment into the mild, moderate, and severe impairment groups are complete with matching controls for comparison. Serum level of total bilirubin and AST will be used to determine which group the hepatic impaired patient will be allocated l. Dosing of the different treatment groups will be staggered. Initially, 6 subjects in Group 1 (normal hepatic function) and 6 subjects in Group 2 will receive a single oral dose of MEK162 on Day 1.
干预措施: MEK162 (Drug)
结局指标
主要结局
PK parameters assessed by Tmax
时间窗: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
Blood pharmacokinetic samples will be collects at various timepoints to assess the MEK162 concentration levels. MEK162 concentrations and preliminary PK parameters will be analyzed in the two groups to determine if a dose adjustment is required in patients with moderate hepatic impairment
PK parameters assessed by Cmax
时间窗: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
Blood pharmacokinetic samples will be collects at various timepoints to assess the MEK162 concentration levels. MEK162 concentrations and preliminary PK parameters will be analyzed in the two groups to determine if a dose adjustment is required in patients with moderate hepatic impairment
PK parameters assessed by AUCinf
时间窗: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
Blood pharmacokinetic samples will be collects at various timepoints to assess the MEK162 concentration levels. MEK162 concentrations and preliminary PK parameters will be analyzed in the two groups to determine if a dose adjustment is required in patients with moderate hepatic impairment
PK parameters assessed by AUC0last
时间窗: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
Blood pharmacokinetic samples will be collects at various timepoints to assess the MEK162 concentration levels. MEK162 concentrations and preliminary PK parameters will be analyzed in the two groups to determine if a dose adjustment is required in patients with moderate hepatic impairment
次要结局
- Relationship between PK parameters versus hepatic function laboratory parameters(Screening, Baseline, Day 2, Day 6 (Day of discharge))
- Number of subjects with adverse events as a measure of safety and tolerability(Screening, Baseline, Day 2, Day 6 (Day of discharge))