Annual Meeting Abstracts: View

  • (Abst. 1.325), 2014
  • ASSESSMENT OF RENAL TOXICITY IN PERAMPANEL-TREATED SUBJECTS: POOLED RESULTS FROM PHASE III CLINICAL STUDIES
  • Authors: Ilo Leppik, Haichen Yang, Betsy Williams, Dongyuan Xing and Antonio Laurenza
  • Content:

    Rationale: The kidney plays an important role in elimination of many drugs, including antiepileptic drugs (AEDs) and their metabolites, making it vulnerable to drug-induced toxicity.1 Treating patients with epilepsy and comorbid renal impairment is challenging and may warrant dose adjustments.2 Perampanel (PER), a selective noncompetitive AMPA receptor antagonist, is approved for adjunctive treatment of partial-onset seizures (POS). Here we report effects of PER on renal laboratory parameters during the Phase III clinical studies and the effect of renal impairment on PER clearance. Methods: Patients with refractory POS enrolled in 3 Phase III studies were aged ≥12yr and receiving 1-3 concomitant AEDs. Following 6wk baseline, patients randomized to 19wk of once-daily DB treatment (6wk titration/13wk maintenance) with PBO or PER 8 or 12mg (Studies 304&305) or PER 2, 4 or 8mg (Study 306). Study results were pooled: 1038 subjects received PER, 442 received PBO. Clinical laboratory tests were performed at baseline and end of treatment. Renal lab parameters included blood urea nitrogen (BUN) and creatinine and were summarized through descriptive statistics, shift tables relative to laboratory normal range, treatment-emergent markedly abnormal values (increase in NCI grade from baseline and Grade ≥2) and adverse events (TEAEs). Effect of renal impairment on PER clearance was evaluated via population pharmacokinetic (PK) model using Phase III data; patients with severe renal impairment were excluded from the studies, so the model included data for patients with normal or mild renal function. Results: Laboratory mean renal values (BUN, creatinine) were within normal ranges at baseline and end of treatment for PBO and all PER groups. Mean changes from baseline to end of treatment were small (Table 1). There were no notable differences between treatment groups (including PBO) and no dose-related trends. No shifts of clinical concern were seen in renal parameters from baseline to end of treatment. Markedly abnormal high values for creatinine were reported in 3 subjects (n=1, PER2mg; n=1, PER12mg; n=1, PBO). This led to early discontinuation for 1 patient (PER 12mg). TEAEs related to renal parameters occurred in 1.8% total PER vs 1.1% PBO. In the population PK model using data from the Phase III studies, median clearance of PER was 27% lower in patients with mild renal impairment compared to patients with normal renal function (Table 2). There was substantial overlap in PER exposure (plasma concentration) between mild renal impairment and normal renal function groups. No data are currently available to support dosing in severe renal impairment or patients undergoing hemodialysis. Conclusions: PER 2, 4, 8 and 12mg demonstrated no clinically important effects on renal function tests, indicating low potential for renal toxicity. Considering the substantial overlap in PER exposure between patients with normal and mild renal impairment, no dosage adjustments are needed. Refs: 1. Decloedt.CME 2011;29:252. 2. Anderson. ClinPharmacokin 2014;53:29. Support: Eisai Inc.
  • Tables:
  • Table 1
  • Table 2