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Pharmacokinetics, exposure-cognition, and exposure-efficacy relationships of perampanel in adolescents with inadequately controlled partial-onset seizures.
- Source :
-
Epilepsy research [Epilepsy Res] 2016 Nov; Vol. 127, pp. 126-134. Date of Electronic Publication: 2016 Aug 22. - Publication Year :
- 2016
-
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.<br />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.<br />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.<br />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.<br /> (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Subjects :
- Administration, Oral
Adolescent
Anticonvulsants adverse effects
Anticonvulsants blood
Attention drug effects
Cognition drug effects
Dose-Response Relationship, Drug
Double-Blind Method
Female
Humans
Male
Memory drug effects
Nitriles
Pyridones adverse effects
Pyridones blood
Seizures blood
Treatment Outcome
Anticonvulsants pharmacokinetics
Anticonvulsants therapeutic use
Pyridones pharmacokinetics
Pyridones therapeutic use
Seizures drug therapy
Seizures psychology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6844
- Volume :
- 127
- Database :
- MEDLINE
- Journal :
- Epilepsy research
- Publication Type :
- Academic Journal
- Accession number :
- 27595590
- Full Text :
- https://doi.org/10.1016/j.eplepsyres.2016.08.025