Concentration-effect relationships with perampanel in patients with
pharmacoresistant partial-onset seizures.
Author(s): Gidal BE(1), Ferry J, Majid O, Hussein Z.
Affiliation(s): Author information:
(1)University of Wisconsin, Madison, Wisconsin 53705, USA. begidal@pharmacy.wisc.edu
Publication date & source: 2013, Epilepsia. , 54(8):1490-7
PURPOSE: 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 first-order 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 reductions in seizure frequency. In addition, increases in
perampanel plasma concentration may potentially be associated with increases in
AE rates. The model-predicted concentration-safety profile of perampanel does not
appear to be affected by patient age, gender, or ethnicity. Although concomitant
EIAEDs may influence perampanel PK, they do not appear to alter the relationship
between perampanel plasma concentration and seizure frequency. Understanding
these relationships between perampanel plasma concentration and clinical response
will be valuable in utilizing this novel AED.
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