Hepatic Impairment
Conditions
Keywords
MEK162, Hepatic impairment, Healthy subjects
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.
Interventions
DRUGMEK162
Sponsors
Array Biopharma, now a wholly owned subsidiary of Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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) * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK parameters assessed by Tmax | 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 | 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 | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Relationship between PK parameters versus hepatic function laboratory parameters | Screening, Baseline, Day 2, Day 6 (Day of discharge) | To explore the relationship between hepatic liver function and PK. Pharmacokinetic parameters will be correlated to hepatic lab parameters. |
| Number of subjects with adverse events as a measure of safety and tolerability | Screening, Baseline, Day 2, Day 6 (Day of discharge) | Adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) grade (severity) and frequency, and other safety data |
Countries
United States
Outcome results
None listed