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Pharmacokinetics, exposure-cognition, and exposure-efficacy relationships of perampanel in adolescents with inadequately controlled partial-onset seizures.

Abstract：

OBJECTIVE:To characterize, in adolescents aged 12-17, the pharmacokinetic (PK) profile of perampanel, the impact of intrinsic and extrinsic factors on PK, and the relationships between perampanel exposure and cognitive function, seizure frequency, and responder status. METHODS:Population PK analysis used plasma concentration data from Phase II study 235 (NCT01161524), in which adolescents with inadequately controlled POS despite treatment with 1-3 antiepileptic drugs (AEDs) were randomized to receive once daily oral placebo or perampanel (8-12mg/day) for 19 weeks, pooled with data from adolescent patients in perampanel Phase III studies 304, 305, 306. Exposure-cognition and exposure-efficacy relationships were modelled using data from study 235. RESULTS:Population PK results from 152 adolescent patients revealed a perampanel apparent clearance of 0.729L/h, consistent with previous analyses in adolescents and adults. Clearance was increased with coadministration of inducing AEDs (carbamazepine, oxcarbazepine and phenytoin), and was slightly higher in females. The PK/pharmacodynamics (PD) analysis for cognition (n=110) showed that increasing perampanel exposure had no significant effect on overall cognition, measured by the Cognitive Drug Research global cognition score. The PK/PD analysis for efficacy (n=123) showed a significant decrease in seizure frequency and significant increased probability of being a responder, as perampanel concentration increased - both in the presence and absence of inducing AEDs. Carbamazepine, oxcarbazepine and phenytoin reduced perampanel exposure in adolescents, but reduced the magnitude of seizure frequency reduction and responder probability to a lesser extent. SIGNIFICANCE:Pharmacokinetics of perampanel are similar in adolescents to adults. Increasing perampanel exposure reduces seizure frequency and increases probability of being a responder regardless of concomitant inducers. The lack of relationship between perampanel exposure and cognitive function suggests a benign cognitive profile for this AED in adolescents. We await results from long-term exposure.

journal_name

Epilepsy Res

journal_title

Epilepsy research

authors

Villanueva V,Majid O,Nabangchang C,Yang H,Laurenza A,Ferry J,Hussein Z

doi

10.1016/j.eplepsyres.2016.08.025

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

126-134

eissn

0920-1211

issn

1872-6844

pii

S0920-1211(16)30145-0

journal_volume

127

pub_type

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Pharmacokinetics, exposure-cognition, and exposure-efficacy relationships of perampanel in adolescents with inadequately controlled partial-onset seizures.