title: Lack of effect of perampanel on QT interval duration: Results from a thorough QT analysis and pooled partial seizure Phase III clinical trials.
abstract: BACKGROUND
  Perampanel is a selective, noncompetitive AMPA receptor antagonist approved as adjunctive treatment for partial seizures. To assess potential for delayed cardiac repolarization, a Phase I thorough QT study was performed, supplemented by plasma concentration-QT data modeled from 3 pooled Phase III studies.
  
  
  METHODS
  The Phase I thorough QT study (double-blind, combined fixed-sequence, parallel-group) quantified the effect of perampanel (6 mg once daily for 7 days, followed by dose escalation to a single 8-mg dose, a single 10-mg dose, then 12 mg once daily for 7 days), moxifloxacin positive control (single 400-mg dose on Day 16), and placebo on QT interval duration in healthy subjects (N = 261). Electrocardiograms were recorded at baseline, Day 7 (post 6 mg dose), and Day 16 (post 12 mg dose). Statistical comparisons were between the highest approved perampanel dose (12 mg) versus placebo, a "mid-therapeutic" dose (6 mg) versus placebo, and moxifloxacin versus placebo. Acknowledging that the Phase I thorough QT study could not incorporate a true "supratherapeutic" dose due to length of titration and tolerability concerns in healthy subjects, Phase III studies of perampanel included expanded electrocardiogram safety evaluations specifically intended to support concentration-QT response modeling. The lack of effect of perampanel on the QT interval is shown from pooled analysis of 3 double-blind, placebo-controlled, 19-week, Phase III studies with perampanel doses ≤ 12 mg (N = 1038, total perampanel; and N=442, placebo) in patients with partial seizures. QT measures were corrected for heart rate using Fridericia's (QTcF; the primary endpoint) and Bazett's (QTcB) formulas.
  
  
  RESULTS
  In the Phase I thorough QT study, the positive control moxifloxacin caused peak time-matched, baseline-adjusted, placebo-corrected (ΔΔ) QTcF of 12.15 ms at 4h postdose, confirming a drug effect on QTc interval and study assessment sensitivity. Mean baseline-adjusted (Δ) QTcF versus nominal time curves were comparable between perampanel 12 mg and placebo, with most ΔQTcF values being slightly negative. Healthy subjects receiving perampanel 6 and 12 mg doses for 7 days showed no evidence of effects on cardiac repolarization. Peak ΔΔQTcF was 2.34 ms at 1.5h postdose for perampanel 6 mg and 3.92 ms at 0.5h postdose for perampanel 12 mg. At every time point, the upper 95% confidence limit of ΔΔQTcF for perampanel 6 and 12 mg was <10 ms. Phase III studies revealed no clinically significant difference between patients with partial seizures treated with perampanel or placebo in QTcF and QTcB values >450 ms, with no dose-dependent increases or large incremental changes from baseline of >60 ms. Regression analysis of individual plasma perampanel concentrations versus corresponding QTc interval values in Phase I thorough QT and Phase III studies demonstrated no relationship between perampanel concentrations and QT interval duration.
  
  
  CONCLUSIONS
  Treatment with perampanel 6 mg and 12 mg for 7 days did not delay cardiac repolarization in healthy volunteers. In a population analysis of 1480 patients with partial seizures treated with perampanel doses ≤ 12 mg or placebo, no clinically significant trends in QT interval data were noted. Based on the thorough QT study and evaluations from pooled Phase III studies, there is no evidence of prolonged QT interval duration with perampanel treatment.
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., Woodcliff Lake, NJ, USA. Electronic address: Haichen_Yang@eisai.com.
authors.forename: Haichen
authors.initials: H
authors.lastname: Yang
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., Woodcliff Lake, NJ, USA. Electronic address: Antonio_Laurenza@eisai.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laurenza
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., Woodcliff Lake, NJ, USA. Electronic address: Betsy_Williams@eisai.com.
authors.forename: Betsy
authors.initials: B
authors.lastname: Williams
authors.affiliation: Eisai Limited, Hatfield, Hertfordshire, UK. Electronic address: Anna_Patten@eisai.net.
authors.forename: Anna
authors.initials: A
authors.lastname: Patten
authors.affiliation: Eisai Limited, Hatfield, Hertfordshire, UK. Electronic address: Ziad_Hussein@eisai.net.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hussein
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., Woodcliff Lake, NJ, USA. Electronic address: Jim_Ferry@eisai.com.
authors.forename: Jim
authors.initials: J
authors.lastname: Ferry
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D004828:Epilepsies, Partial / Q000150:complications* / Q000188:drug therapy; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009570:Nitriles; D011728:Pyridones / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012016:Reference Values; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D024841:Fluoroquinolones; D009570:Nitriles; D011728:Pyridones; C551441:perampanel; D000077266:Moxifloxacin
keywords: Antiepileptic drugs; Cardiac; Partial seizures; Perampanel; QT interval; Thorough QT