Normal Hepatic Function, Severe Hepatic Impairment
Conditions
Keywords
Phase 1, Pharmacokinetics, Safety, Severe hepatic impairment, Enzalutamide
Brief summary
The influence of severely diminished liver function on the metabolism, safety, and tolerability of a single oral dose of enzalutamide in a group of 8 men. The results are compared to the data gained from 8 age- and BMI-matched men with normal liver function.
Detailed description
Screening takes place between Day -22 and Day -2, and subjects are admitted to the clinic on Day -1. Each subject receives a single oral dose of enzalutamide on Day 1, under fasted conditions. They are discharged on Day 7; ambulant visits take place until Day 50. An End of Study Visit (ESV) occurs 7-10 days after the last PK sampling or early withdrawal. Full PK profiles are obtained for enzalutamide, metabolite 1 of enzalutamide (M1) and metabolite 2 of enzalutamide (M2) up to 1176 hours (Day 50) after administration. Safety assessments are performed throughout the study. For subjects with severe hepatic impairment, additional Child-Pugh classification and laboratory safety tests (including liver function tests) are performed regularly after administration.
Interventions
DRUGenzalutamide
oral
Sponsors
Medivation, Inc.
Astellas Pharma Europe B.V.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 69 Years
Healthy volunteers
Yes
Inclusion criteria
* Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control starting at Screening and continue throughout the study period and for 90 days after the final study drug administration. * Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration. * Subject has a Body Mass Index (BMI) range of 18.5 - 34.0 kg/m2 inclusive. The subject weighs at least 50 kg \[at Screening\]. Inclusion Criteria:Subjects with severe hepatic impairment must also meet the following inclusion criteria: * Subject has a Child-Pugh classification Class C (severe, 10 to 15 points). Inclusion Criteria: For Healthy Subjects Only: * Age- and BMI-matched to subjects with severe liver hepatic impairment.
Exclusion criteria
* Subject has known or suspected hypersensitivity to enzalutamide, or any components of the formulation used. * Subject has history of seizure or any condition that may predispose to seizure. Also history of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 visit). * Subject has used grapefruit (or grapefruit containing products) or marmalade in the week prior to admission to the clinical unit (Day -1), as reported by the subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of enzalutamide after a single oral dose | Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50 | area under the plasma concentration - time curve (AUC) extrapolated to infinity (AUC0-inf) |
| PK of enzalutamide after a single oral dose | Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50 | maximum concentration (observed) (Cmax) |
| PK of enzalutamide plus N-desmethyl enzalutamide (M2) after a single oral dose | Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50 | area under the plasma concentration - time curve (AUC) extrapolated to infinity (AUC0-inf) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK of enzalutamide, M1, M2 and the sum of enzalutamide plus N-desmethyl enzalutamide (M2) | Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50 | Cmax and AUC0-inf (M1, M2 only), time to attain Cmax (tmax), AUC up to last quantifiable concentration (AUC0-last), apparent terminal elimination half life (t1/2), apparent volume of distribution during the terminal phase after extra vascular dosing (Vz/F), apparent total body clearance after extra vascular dosing (CL/F) (parent compound only), Metabolite-to-Parent Ratio (MPR), percent extrapolated for AUC0-inf (%AUC) |
| Additional pharmacokinetic variables for enzalutamide, and, as appropriate, for M1 and M2, based upon unbound plasma concentrations | Days 1-6, 8, 12, 15, 19, 22, 26, 29, 36, 43, 50 | Unbound Cmax (Cmax,u), unbound AUC0-inf (AUC0-inf,u), and unbound AUC0-last (AUC0-last,u). Unbound CL/F (CLu/F) and unbound Vz/F (Vz,u/F) (parent only) |
Countries
Bulgaria
Outcome results
None listed