PHARMACOKINETICS OF PERAMPANEL: RESULTS FROM PHASE I CLINICAL PHARMACOLOGY STUDIES
Abstract number :
1.143
Submission category :
4. Clinical Epilepsy
Year :
2013
Submission ID :
1736800
Source :
www.aesnet.org
Presentation date :
12/7/2013 12:00:00 AM
Published date :
Dec 5, 2013, 06:00 AM
Authors :
B. Gidal, A. Laurenza, H. Yang, B. Williams, D. A. Verbel, J. Ferry
Rationale: Perampanel (PER) is a selective, noncompetitive AMPA-antagonist that has been approved as adjunctive treatment for partial-onset seizures. Twenty-seven phase I clinical pharmacology studies were designed to establish the pharmacokinetic (PK) profile of PER. Here we report the results from 14 phase I studies on PER PK, specifically, absorption, distribution, metabolism and excretion, and dose proportionality.Methods: In 14 phase I studies, single doses of PER ranging from 0.2 to 12mg or once-daily doses of PER ranging from 1 to 12mg were administered to healthy male and female volunteers to investigate PER PK. Validated bioanalytical methods were used to analyze drug concentrations of biological samples collected in the basic PK studies. Effect of food on PER PK was determined via single-dose studies (1mg PER, or 6mg PER vs placebo) in fed (high-fat meal) or fasting conditions. Also investigated were mass balance (single-dose, oral administration of 2mg PER radiolabeled with 200nCi of 14C-PER), absolute oral bioavailability and metabolite profile of PER [single-dose, oral administration of 8mg PER and single microdose of 10 g (200nCi) 14C-PER administered intravenously 45 min later].Results: Following oral administration, PER (tablet and suspension) is rapidly and essentially completely absorbed with a median time to maximal peak concentration (tmax) of 0.75h (0.5-1h). Dosing with food consistently slows PER absorption (tmax 3h later in fed vs fasted state), and reduces maximal peak concentrations (Cmax) by 28%, but it does not reduce the overall extent of PER absorption. PER displays an initial decline in plasma concentrations over 12h, and it appears to be eliminated in a bi- or tri-exponential manner, with a long terminal elimination phase. PER is approximately 95% bound to plasma proteins. In single-dose studies, reported mean terminal elimination half-lives (t1/2) ranged from 53 to 136h across studies and dose groups. PER is extensively metabolized via CYP3A4, with the main metabolic pathway being oxidation at the pyridine, benzene, or benzonitrile rings and subsequent glucuronide conjugation. Consistent with its long elimination t1/2, accumulation was evident with multiple-dose administration, and PER exposure at steady state was substantially higher than after a single dose. Renal elimination of PER is minimal, with <0.12% of an administered dose eliminated unchanged in urine. In subjects with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, unbound systemic exposure (AUC0- ) of PER was 1.8- to 3.3-fold higher, and t1/2 was approximately 2-fold longer than in control subjects.Conclusions: Phase I studies conducted in healthy subjects over a wide range of PER doses established basic PK, effects of food on PK, and metabolic profile. Taken together, these studies suggest PER displays consistent linear PK over the therapeutic dose range (4 12mg). These studies have provided clinical pharmacology data contributing to safe and effective use of PER in epilepsy patients with partial-onset seizures.
Clinical Epilepsy