Concentration–effect relationships with perampanel in patients with pharmacoresistant partial‐onset seizures

Abstract

SUMMARYPurpose: Although there is a general paucity of published pharmacokinetic (PK) data for new antiepileptic drugs (AEDs), PK analyses of pooled data from clinical studies of perampanel have recently been presented. We present PK/pharmacodynamic (PD) analyses of pooled data from phase III studies of perampanel describing efficacy and safety as a function of exposure, in order to determine whether a predictable concentration-effect relationship exists for perampanel efficacy and/or adverse events (AEs). The effects of concomitant enzyme-inducing AEDs (EIAEDs) and non-enzyme-inducing AEDs on the exposure, efficacy, and safety of perampanel are also considered. Methods: Three multicenter, randomized, double-blind, placebo-controlled phase III studies investigated the efficacy and safety of perampanel 2-12 mg in patients with uncontrolled partial-onset seizures despite prior therapy with two or more AEDs. From baseline onward, patients also received ongoing treatment with stable doses of one to three approved concomitant AEDs. AEs were monitored throughout the studies. Changes from baseline in seizure frequency and 50% responder rates were evaluated. Exposure to perampanel was predicted based on the actual (last) dose using a previously established PK model. A population PK/PD model for the relationship between perampanel exposure and seizure frequency was estimated using nonlinear mixed-effect modeling with firstorder conditional estimation, whereas logistic analyses for responder rate and AEs were performed using SAS analysis software. Key Findings: The PK/PD population included 1,109 patients. Seizure frequency decreased linearly as predicted perampanel average steady-state plasma concentrations increased. Concomitant EIAEDs (carbamazepine, oxcarbazepine, and phenytoin) reduced exposure to perampanel but had no effect on the slope of the PD model-predicted relationship between exposure and reduction in seizure frequency. The probability of patients achieving a response was predicted to increase as perampanel average plasma concentration at steady state increased. No demographic, AED, region, or study covariate had any effect on the probability of achieving a positive treatment response to perampanel or on the slope of the exposure-response curve. Across the phase III studies, there were reports of dizziness (32.9%), somnolence (21.7%), fatigue (13.9%), irritability (12.3%), gait disturbance (9.1%), weight increase (6.1%), dysarthria (4.5%), and euphoric mood (0.5%); the model-predicted probability of these AEs increased significantly at higher exposure to perampanel (all p < 0.001). There was no effect of demographic variables or region on the probability of experiencing any of the AEs analyzed. Significance: PK and PD analyses have played a pivotal role in the clinical development of perampanel as an adjunctive treatment for pharmacoresistant partial-onset seizures. Phase III data suggest that a significant relationship exists between increases in perampanel plasma concentration (i.e., systemic exposure) and...

Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures

“…The lower clearance and corresponding increase in perampanel plasma concentrations in female subjects may provide a basis for the slightly greater seizure reduction seen in female subjects with therapeutic doses (4–12 mg) of perampanel. A linear relationship has indeed been demonstrated between perampanel systemic exposure and its PD effects 8. At all doses of perampanel studied, both male and female participants exhibited reductions in seizure frequency compared to placebo, although at the 8 mg dose, a significant difference was observed between genders for the median percent change.…”

“…The final PK model, using a one‐compartment disposition model with first‐order elimination to describe perampanel plasma concentrations at steady state, yielded adequate predictions of pooled data from the perampanel phase III studies 8. This was considered an appropriate basis for predicting perampanel exposure in exposure–response PK/PD analyses 8.…”

Analysis of pooled phase III trials of adjunctive perampanel for epilepsy: Impact of mechanism of action and pharmacokinetics on clinical outcomes

“…Approval was based on three placebo-controlled phase III pivotal studies in a total of 1480 patients with refractory partial-onset seizures who were receiving 1-3 concomitant AEDs (French et al, , 2013Krauss et al, 2012). As expected from the metabolism of perampanel by CYP3A4 (European Medicines Agency, 2012), pooled data from these studies indicated that enzyme-inducing AEDs (EIAEDs) reduced perampanel plasma concentrations without affecting the relationship between plasma concentration and reduction in seizure frequency (Gidal et al, 2013). This was consistent with the pharmacokinetic effects of hepatic enzyme induction/inhibition previously reported in the literature (Johannessen Landmark et al, 2012;Patsalos, 2013).…”

The discovery and development of perampanel for the treatment of epilepsy

“…Among frequent AEs and AEs of special interest, the predicted probability of dizziness, somnolence, fatigue, irritability, gait disturbance, weight increase, dysarthia and euphoric mood were increased significantly in patients with higher plasma concentrations of perampanel compared with those patients who had lower plasma concentrations of perampanel (p < 0.001) [59]. In general, concomitant AEDs were not found to have any effect on the frequency of AEs.…”

“…Pharmacokinetic/pharmacodynamic analyses of the pooled Phase III data have indicated a significant linear relationship between perampanel plasma concentrations and efficacy [59]. This relationship was not affected by the presence or absence of specific concomitant AEDs, although perampanel plasma concentrations were reduced by AEDs known to induce the CYP3A4 enzyme, which plays a key role in the hepatic metabolism and elimination of perampanel.…”