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Pharmacokinetic/pharmacodynamic analysis of adjunctive perampanel in subjects with partial‐onset seizures
Author(s) -
Takenaka O.,
Ferry J.,
Saeki K.,
Laurenza A.
Publication year - 2018
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/ane.12874
Subject(s) - perampanel , pharmacodynamics , epilepsy , population , medicine , oxcarbazepine , placebo , carbamazepine , pharmacokinetics , anesthesia , pharmacology , psychiatry , alternative medicine , environmental health , pathology
Objectives Explore perampanel pharmacokinetics ( PK ) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial‐onset seizures ( POS ) and identify factors explaining between‐subject variability in efficacy using a population PK /pharmacodynamic ( PD ) analysis. Materials & methods Population PK analysis was performed using nonlinear mixed‐effect modeling with data from phase II / III randomized, double‐blind, placebo‐controlled studies of adjunctive perampanel in POS . Perampanel exposure was predicted for all subjects and adolescents. Population PK / PD analyses were performed using data from phase III studies to explore the relationship between perampanel exposure and 28‐day average seizure frequency and responder probability. Results Pooled perampanel PK data from 1318 subjects were described by a one‐compartment disposition model. In the absence of antiepileptic drugs ( AED s) affecting perampanel PK , estimated perampanel apparent clearance ( CL /F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co‐administration of carbamazepine and oxcarbazepine/phenytoin reduced perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered perampanel CL /F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK / PD data from 1748 subjects, percent reduction in 28‐day average seizure frequency from baseline and responder probability increased with increasing perampanel exposure; concomitant CYP 3A‐inducing AED s lowered perampanel exposure but did not impact the slope for responder probability. Conclusions These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.