A Phase I, Multicenter, Open-label, Single-dose Study to Assess the Pharmacokinetics of MEK162 in Subjects With Mild, Moderate and Severe Hepatic Impairment
Overview
- Phase
- Phase 1
- Intervention
- MEK162
- Conditions
- Hepatic Impairment
- Sponsor
- Array Biopharma, now a wholly owned subsidiary of Pfizer
- Enrollment
- 27
- Locations
- 5
- Primary Endpoint
- PK parameters assessed by Tmax
- Status
- Terminated
- Last Updated
- 5 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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)
Arms & Interventions
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.
Intervention: MEK162
Outcomes
Primary Outcomes
PK parameters assessed by Tmax
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Secondary Outcomes
- 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))