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Antonio Laurenza - One of the best experts on this subject based on the ideXlab platform.

  • Potential protein-binding displacement interactions with Perampanel: An in vitro analysis.
    Epilepsy research, 2018
    Co-Authors: Barry E Gidal, Antonio Laurenza, Jim Ferry, Takashi Ueno
    Abstract:

    Abstract Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug–drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t½ is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine Perampanel’s potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace Perampanel. Protein binding of Perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of Perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, Perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of Perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate Perampanel has low potential for drug interactions resulting from protein-binding displacement.

  • 055 effect of common concomitant antiepileptic drugs during adjunctive treatment with Perampanel post hoc analysis from the open label extension of a phase iii study in patients with idiopathic generalised epilepsy
    Journal of Neurology Neurosurgery and Psychiatry, 2018
    Co-Authors: Terence J Obrien, Francesco Bibbiani, Anna Patten, Antonio Laurenza, Betsy Williams
    Abstract:

    Introduction Perampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic (PGTC) seizures in epilepsy patients aged ≥12 years. Perampanel is also approved for monotherapy use for partial seizures in the US. This post hoc analysis assessed the effects of the most common concomitant Baseline antiepileptic drugs (AEDs) on discontinuation rates and treatment-emergent adverse event (TEAE) incidence during adjunctive treatment with Perampanel in patients (aged ≥12 years) with idiopathic generalised epilepsy (IGE) and PGTC seizures in the open-label extension (OLEx) Phase of Study 332 (NCT02307578). Methods Patients completing the double-blind study could receive Perampanel (≤12 mg/day) during the OLEx (6 week blinded Conversion Period;≤136 weeks’ Maintenance). Here, we report results for Perampanel >4–8 mg/day and >8–12 mg/day. Results Most common concomitant Baseline AEDs were valproic acid (n=55), lamotrigine (n=53), levetiracetam (n=37), topiramate (n=21) and zonisamide (n=12); patients may have received >1 of these Baseline AEDs. The most common reasons for discontinuing were adverse event(s) (AE), ‘other’ and patient choice. Lamotrigine: patient choice, n=6/34 (>4–8 mg/day); AE/‘other’, both n=3/19 (>8–12 mg/day). Levetiracetam: patient choice, n=5/27 (>4–8 mg/day); AE, n=2/10 (>8–12 mg/day). Topiramate: ‘other’, n=3/15 (>4–8 mg/day); AE/‘other’, both n=1/6 (>8–12 mg/day). Valproic acid: patient choice, n=6/38 (>4–8 mg/day); ‘other’, n=4/17 (>8–12 mg/day). Zonisamide: patient choice/‘other’, both n=2/10 (>4–8 mg/day); no discontinuations (>8–12 mg/day). Patient-reported TEAEs ranged from: 88.2% (lamotrigine) to 93.3% (topiramate) for Perampanel >4–8 mg/day, and 70.6% (valproic acid) to 100.0% (topiramate and zonisamide) for Perampanel >8–12 mg/day. The most common TEAE was dizziness. Conclusion In this post hoc analysis, primary reasons for discontinuation and TEAE incidence differed between the most common Baseline AED subgroups and Perampanel dose range, although TEAE types were similar. These data provide additional information on the safety of adjunctive Perampanel in patients with IGE. Study support Eisai Inc.

  • pharmacokinetic pharmacodynamic analysis of adjunctive Perampanel in subjects with partial onset seizures
    Acta Neurologica Scandinavica, 2018
    Co-Authors: O. Takenaka, Jim Ferry, K. Saeki, Antonio Laurenza
    Abstract:

    OBJECTIVES Explore Perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis. MATERIALS & METHODS Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive Perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between Perampanel exposure and 28-day average seizure frequency and responder probability. RESULTS Pooled Perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting Perampanel PK, estimated Perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced Perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered Perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing Perampanel exposure; concomitant CYP3A-inducing AEDs lowered Perampanel exposure but did not impact the slope for responder probability. CONCLUSIONS These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

  • PO045 Perampanel as monotherapy in open-label extension studies
    Journal of Neurology Neurosurgery & Psychiatry, 2017
    Co-Authors: Patrick Kwan, Anna Patten, Antonio Laurenza, Scott Mintzer, Karen Cartwright
    Abstract:

    Background Perampanel, a selective, non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondary generalised seizures, and for primary generalised tonic-clonic seizures in patients with epilepsy aged ≥12 years. Methods We analysed the seizure outcomes of individuals with focal seizures who discontinued all non-Perampanel antiepileptic drugs (AEDs) and continued to receive Perampanel (up to 12 mg/day) as monotherapy in two open-label extension (OLEx) studies: Study 307 (NCT00735397) and the Study 235 OLEx (NCT01161524). Results Seven patients discontinued all concomitant AEDs and took Perampanel as monotherapy (Study 307, n=6; Study 235 OLE, n=1; female, n=1; age range, 15–40 years) for up to 1099 days (157 weeks). Seizure data were available for six patients, of whom five had a≥90% reduction in overall seizure frequency between baseline and their last 13 week period of monotherapy (three were seizure-free). Five patients experienced treatment-emergent adverse events (TEAEs) during Perampanel monotherapy; no TEAEs occurred in more than one patient. There were no deaths and only one serious TEAE (colitis), which was not considered related to Perampanel treatment.

  • Evaluation of Perampanel as monotherapy for focal seizures: Experience from open-label extension studies
    Epilepsy & behavior case reports, 2017
    Co-Authors: Patrick Kwan, Anna Patten, Antonio Laurenza, Scott Mintzer, Karen Cartwright
    Abstract:

    Abstract Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic–clonic seizures in patients with epilepsy aged ≥ 12 years. Perampanel was recently approved for monotherapy use for focal seizures in the U.S.A. Anti-seizure drug monotherapy may be preferable to polytherapy, which is generally associated with increased toxicity, non-compliance, and cost. Here, we report cases where patients had converted to Perampanel monotherapy during open-label extension (OLEx) portions of 9 Phase II and III studies. Of 2245 patients who enrolled in the OLEx studies, we identified 7 patients with drug-resistant focal seizures who discontinued all non-Perampanel anti-seizure drugs and were maintained on Perampanel monotherapy for ≥ 91 days until the end of data cut-off. Patients received Perampanel monotherapy for up to 1099 days (157 weeks), most at a modal dose of 12 mg. Seizure data were available for 6 patients, of whom 5 had a ≥ 90% reduction in overall seizure frequency between baseline and their last 13-week period of monotherapy (3 were seizure-free). Perampanel monotherapy was generally well tolerated and the safety profile during Perampanel monotherapy was consistent with clinical and post-marketing experience in the adjunctive setting. This analysis included a small proportion of patients with highly drug-resistant focal seizures who converted to monotherapy during OLEx studies. While these limited data are encouraging in suggesting that Perampanel might be useful as a monotherapy, further studies are required to explore outcomes in a less drug-resistant population, where a larger proportion of patients might benefit from monotherapy.

Haichen Yang - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Enzyme Inhibition on Perampanel Pharmacokinetics: Why Study Design Matters
    Epilepsy research, 2017
    Co-Authors: Barry E Gidal, Antonio Laurenza, Haichen Yang, Edgar Schuck, Rama Maganti, David Verbel, Jim Ferry
    Abstract:

    Abstract Objectives Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that Perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t 1/2 ) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions—enzyme inhibition or induction—and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining Perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. Methods A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of Perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg Perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the Perampanel dose. Pharmacokinetic parameters of Perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp ® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of Perampanel in the presence or absence of concomitant ketoconazole. Results Single oral doses of 1mg Perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum Perampanel plasma concentration (C max ) and time to C max showed no apparent differences when Perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in Perampanel AUC ( P 0.001). This increase, although statistically significant, was a 2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of Perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. Conclusions Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as Perampanel that have a long t 1/2 . Although a negligible effect on Perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and Perampanel ( 1/2 of Perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase Perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.

  • analysis of falls in patients with epilepsy enrolled in the Perampanel phase iii randomized double blind studies
    Epilepsia, 2017
    Co-Authors: Ilo E Leppik, Francesco Bibbiani, Anna Patten, Betsy Williams, Haichen Yang, Sharon Zhou, Randi Fain, Antonio Laurenza
    Abstract:

    SummaryObjective To analyze occurrence of falls among patients with partial seizures, with/without secondarily generalized seizures (SGS), and primary generalized tonic–clonic seizures (PGTCS) in the Perampanel phase III clinical studies. Methods Studies 304, 305, and 306 randomized subjects (≥12 years) with drug-resistant partial seizures (with/without SGS) to Perampanel 2, 4, 8, or 12 mg or placebo for double-blind treatment. The adverse event (AE) of falls was analyzed in the Safety Analysis Set (N = 1480). Study 332 randomized subjects aged ≥12 years with a diagnosis of PGTCS into Perampanel 8 mg or placebo groups for double-blind treatment. In a systematic review of reported falls in the study 332 Safety Analysis Set (N = 163), falls were queried to establish whether each was seizure related; subjects with falls resulting from a seizure were not included in this analysis. Results For studies 304/305/306, treatment-emergent falls occurred in 5.1% Perampanel-treated versus 3.4% placebo-treated subjects with partial seizures. Exposure-adjusted rate for falls (falls/subject-month of exposure) was greater for total Perampanel than for placebo (0.0175 vs. 0.0093) and was dose related for those receiving Perampanel. In subjects with SGS, incidence of treatment-emergent falls was 4.3% in Perampanel and 4.0% in placebo groups. Exposure-adjusted rates were 0.0169 and 0.0097 falls per subject-month of exposure in Perampanel and placebo, respectively. For study 332, 2.5% Perampanel-treated and 1.2% placebo-treated subjects with PGTCS had treatment-emergent falls that were not part of a seizure. Exposure-adjusted rates were 0.0169 and 0.0032 falls per subject-month of exposure in Perampanel and placebo, respectively. Significance Results of the Perampanel studies suggest that patients with epilepsy should be monitored due to the common risk of falls.

  • PSYCHIATRIC/BEHAVIOURAL EVENTS WITH Perampanel TREATMENT FOR PGTCS
    Journal of Neurology Neurosurgery & Psychiatry, 2016
    Co-Authors: Cindy Dobrinsky, Anna Patten, Betsy Williams, Antonio Laurenza, Haichen Yang, Alan B. Ettinger, William Rosenfeld, Francesco Bibbiani
    Abstract:

    Purpose To review psychiatric and behavioural events in a study conducted to evaluate the efficacy and safety of adjunctive Perampanel in patients with uncontrolled primary generalised tonic-clonic seizures (PGTCS). Method Following baseline (4 or 8 weeks), patients aged ≥12 years were randomised to double-blind treatment with Perampanel or placebo (titration 4 weeks; maintenance 13 weeks; maximum dose 8 mg). Treatment-emergent adverse events (TEAEs) were evaluated using MedDRA search terms for psychiatric disorders and MedDRA SMQs for hostility/aggression-related events. Results In the Safety Analysis Set (Perampanel n=81; placebo n=82), psychiatric TEAEs occurred in 20 (24.7%) Perampanel- and 16 (19.5%) placebo-treated patients. Most TEAEs were of mild or moderate intensity. Frequency of TEAEs related to hostility/aggression was 18.5% for Perampanel and 4.9% for placebo, largely due to a higher rate of irritability with Perampanel (11.1%) versus placebo (2.4%). Incidences of serious adverse events and discontinuations due to TEAEs related to hostility/aggression for Perampanel versus placebo were 1.2% versus 0% and 3.7% versus 1.2%, respectively. Conclusion Consistent with results from Phase III trials in partial epilepsy, hostility/aggression-related TEAEs occurred at a higher rate in Perampanel-treated patients with PGTCS than in those treated with placebo, driven mainly by irritability. Supported by Eisai Inc.

  • Perampanel TREATMENT FOR GENERALISED TONIC-CLONIC SEIZURES
    Journal of Neurology Neurosurgery & Psychiatry, 2016
    Co-Authors: Terence J. O'brien, Francesco Bibbiani, Anna Patten, Betsy Williams, Haichen Yang, Antonio Laurenza
    Abstract:

    Purpose A post hoc analysis evaluated the efficacy and tolerability of Perampanel across four Phase III studies in patients with secondarily generalised (SG) or primary generalised tonic-clonic (PGTC) seizures. Method All studies involved patients aged ≥12 years. Studies 304 (n=388) and 305 (n=386) evaluated Perampanel 8 or 12 mg/day or placebo. Study 306 (n=706) evaluated Perampanel 2, 4, or 8 mg/day or placebo. These studies had a 19-week double-blind phase (6-week titration; 13-week maintenance). Study 332 (n=164) evaluated Perampanel up to 8 mg/day or placebo (17-week double-blind phase; 4-week titration, 13-week maintenance). Full Analysis Set (FAS) included patients who had SG or PGTC seizures and received Perampanel 8 mg/day. Results FAS included 492 patients (mean age 31.7 years). Compared with placebo, Perampanel conferred a greater median percent reduction in PGTC/SG seizure frequency per 28 days (−24.6% vs. −65.5%; p Conclusion Perampanel reduced generalised tonic-clonic seizure frequency, whether primary or SG, and was well tolerated. Funded by Eisai Inc.

  • Pharmacokinetics, exposure-cognition, and exposure-efficacy relationships of Perampanel in adolescents with inadequately controlled partial-onset seizures.
    Epilepsy research, 2016
    Co-Authors: Vicente Villanueva, Antonio Laurenza, Haichen Yang, Jim Ferry, Charcrin Nabangchang, Oneeb Majid, Ziad Hussein
    Abstract:

    Abstract Objective To characterize, in adolescents aged 12–17, the pharmacokinetic (PK) profile of Perampanel, the impact of intrinsic and extrinsic factors on PK, and the relationships between Perampanel exposure and cognitive function, seizure frequency, and responder status. Methods Population PK analysis used plasma concentration data from Phase II study 235 (NCT01161524), in which adolescents with inadequately controlled POS despite treatment with 1–3 antiepileptic drugs (AEDs) were randomized to receive once daily oral placebo or Perampanel (8–12mg/day) for 19 weeks, pooled with data from adolescent patients in Perampanel Phase III studies 304, 305, 306. Exposure–cognition and exposure–efficacy relationships were modelled using data from study 235. Results Population PK results from 152 adolescent patients revealed a Perampanel apparent clearance of 0.729L/h, consistent with previous analyses in adolescents and adults. Clearance was increased with coadministration of inducing AEDs (carbamazepine, oxcarbazepine and phenytoin), and was slightly higher in females. The PK/pharmacodynamics (PD) analysis for cognition (n=110) showed that increasing Perampanel exposure had no significant effect on overall cognition, measured by the Cognitive Drug Research global cognition score. The PK/PD analysis for efficacy (n=123) showed a significant decrease in seizure frequency and significant increased probability of being a responder, as Perampanel concentration increased − both in the presence and absence of inducing AEDs. Carbamazepine, oxcarbazepine and phenytoin reduced Perampanel exposure in adolescents, but reduced the magnitude of seizure frequency reduction and responder probability to a lesser extent. Significance: Pharmacokinetics of Perampanel are similar in adolescents to adults. Increasing Perampanel exposure reduces seizure frequency and increases probability of being a responder regardless of concomitant inducers. The lack of relationship between Perampanel exposure and cognitive function suggests a benign cognitive profile for this AED in adolescents. We await results from long-term exposure.

Anna Patten - One of the best experts on this subject based on the ideXlab platform.

  • A systematic review and indirect treatment comparison of Perampanel versus brivaracetam as adjunctive therapy in patients with focal-onset seizures with or without secondary generalization.
    Epilepsy research, 2020
    Co-Authors: Eugen Trinka, Anna Patten, Wan Tsong, Sydney Toupin, Katy Wilson, Jaana Isojarvi, Daniel James
    Abstract:

    Abstract Purpose To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of Perampanel to brivaracetam in the adjunctive treatment of focal-onset seizures. This study makes these comparisons through the use of indirect treatment comparison (ITC) methods. Methods A systematic review was conducted to identify RCTs that evaluated either one of Perampanel or brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was then used to compare efficacy and safety outcomes between Perampanel and brivaracetam. Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted. Results Eight RCTs (four comparing Perampanel to placebo, four comparing brivaracetam to placebo) were included in the ITC. For patients taking concomitant levetiracetam, Perampanel showed a significantly better responder rate compared to brivaracetam [relative risk (RR) and 95 % confidence interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both Perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between Perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking Perampanel. No differences for any other safety outcome were found. Conclusion Perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam.

  • 055 effect of common concomitant antiepileptic drugs during adjunctive treatment with Perampanel post hoc analysis from the open label extension of a phase iii study in patients with idiopathic generalised epilepsy
    Journal of Neurology Neurosurgery and Psychiatry, 2018
    Co-Authors: Terence J Obrien, Francesco Bibbiani, Anna Patten, Antonio Laurenza, Betsy Williams
    Abstract:

    Introduction Perampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic (PGTC) seizures in epilepsy patients aged ≥12 years. Perampanel is also approved for monotherapy use for partial seizures in the US. This post hoc analysis assessed the effects of the most common concomitant Baseline antiepileptic drugs (AEDs) on discontinuation rates and treatment-emergent adverse event (TEAE) incidence during adjunctive treatment with Perampanel in patients (aged ≥12 years) with idiopathic generalised epilepsy (IGE) and PGTC seizures in the open-label extension (OLEx) Phase of Study 332 (NCT02307578). Methods Patients completing the double-blind study could receive Perampanel (≤12 mg/day) during the OLEx (6 week blinded Conversion Period;≤136 weeks’ Maintenance). Here, we report results for Perampanel >4–8 mg/day and >8–12 mg/day. Results Most common concomitant Baseline AEDs were valproic acid (n=55), lamotrigine (n=53), levetiracetam (n=37), topiramate (n=21) and zonisamide (n=12); patients may have received >1 of these Baseline AEDs. The most common reasons for discontinuing were adverse event(s) (AE), ‘other’ and patient choice. Lamotrigine: patient choice, n=6/34 (>4–8 mg/day); AE/‘other’, both n=3/19 (>8–12 mg/day). Levetiracetam: patient choice, n=5/27 (>4–8 mg/day); AE, n=2/10 (>8–12 mg/day). Topiramate: ‘other’, n=3/15 (>4–8 mg/day); AE/‘other’, both n=1/6 (>8–12 mg/day). Valproic acid: patient choice, n=6/38 (>4–8 mg/day); ‘other’, n=4/17 (>8–12 mg/day). Zonisamide: patient choice/‘other’, both n=2/10 (>4–8 mg/day); no discontinuations (>8–12 mg/day). Patient-reported TEAEs ranged from: 88.2% (lamotrigine) to 93.3% (topiramate) for Perampanel >4–8 mg/day, and 70.6% (valproic acid) to 100.0% (topiramate and zonisamide) for Perampanel >8–12 mg/day. The most common TEAE was dizziness. Conclusion In this post hoc analysis, primary reasons for discontinuation and TEAE incidence differed between the most common Baseline AED subgroups and Perampanel dose range, although TEAE types were similar. These data provide additional information on the safety of adjunctive Perampanel in patients with IGE. Study support Eisai Inc.

  • Evaluation of Perampanel as monotherapy for focal seizures: Experience from open-label extension studies
    Epilepsy & behavior case reports, 2017
    Co-Authors: Patrick Kwan, Anna Patten, Antonio Laurenza, Scott Mintzer, Karen Cartwright
    Abstract:

    Abstract Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic–clonic seizures in patients with epilepsy aged ≥ 12 years. Perampanel was recently approved for monotherapy use for focal seizures in the U.S.A. Anti-seizure drug monotherapy may be preferable to polytherapy, which is generally associated with increased toxicity, non-compliance, and cost. Here, we report cases where patients had converted to Perampanel monotherapy during open-label extension (OLEx) portions of 9 Phase II and III studies. Of 2245 patients who enrolled in the OLEx studies, we identified 7 patients with drug-resistant focal seizures who discontinued all non-Perampanel anti-seizure drugs and were maintained on Perampanel monotherapy for ≥ 91 days until the end of data cut-off. Patients received Perampanel monotherapy for up to 1099 days (157 weeks), most at a modal dose of 12 mg. Seizure data were available for 6 patients, of whom 5 had a ≥ 90% reduction in overall seizure frequency between baseline and their last 13-week period of monotherapy (3 were seizure-free). Perampanel monotherapy was generally well tolerated and the safety profile during Perampanel monotherapy was consistent with clinical and post-marketing experience in the adjunctive setting. This analysis included a small proportion of patients with highly drug-resistant focal seizures who converted to monotherapy during OLEx studies. While these limited data are encouraging in suggesting that Perampanel might be useful as a monotherapy, further studies are required to explore outcomes in a less drug-resistant population, where a larger proportion of patients might benefit from monotherapy.

  • PO045 Perampanel as monotherapy in open-label extension studies
    Journal of Neurology Neurosurgery & Psychiatry, 2017
    Co-Authors: Patrick Kwan, Anna Patten, Antonio Laurenza, Scott Mintzer, Karen Cartwright
    Abstract:

    Background Perampanel, a selective, non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondary generalised seizures, and for primary generalised tonic-clonic seizures in patients with epilepsy aged ≥12 years. Methods We analysed the seizure outcomes of individuals with focal seizures who discontinued all non-Perampanel antiepileptic drugs (AEDs) and continued to receive Perampanel (up to 12 mg/day) as monotherapy in two open-label extension (OLEx) studies: Study 307 (NCT00735397) and the Study 235 OLEx (NCT01161524). Results Seven patients discontinued all concomitant AEDs and took Perampanel as monotherapy (Study 307, n=6; Study 235 OLE, n=1; female, n=1; age range, 15–40 years) for up to 1099 days (157 weeks). Seizure data were available for six patients, of whom five had a≥90% reduction in overall seizure frequency between baseline and their last 13 week period of monotherapy (three were seizure-free). Five patients experienced treatment-emergent adverse events (TEAEs) during Perampanel monotherapy; no TEAEs occurred in more than one patient. There were no deaths and only one serious TEAE (colitis), which was not considered related to Perampanel treatment.

  • A retrospective, multicentre study of Perampanel given as monotherapy in routine clinical care in people with epilepsy
    Seizure, 2017
    Co-Authors: Antonio Gil-nagel, Anna Patten, Manuel Toledo, Sergey Burd, Josemir W. Sander, A. V. Lebedeva, Antonio Laurenza
    Abstract:

    Abstract Purpose Perampanel is approved for adjunctive treatment of focal seizures, with or without secondarily generalised seizures, and for primary generalised tonic-clonic seizures in people with epilepsy aged ≥12 years. Perampanel was recently approved for monotherapy use for partial seizures in the United States. This study provides insight into the feasibility of Perampanel monotherapy in real-world settings. Methods This retrospective, non-interventional, multicentre study (NCT02736162) was conducted between January 2013 and March 2016 in specialist epilepsy centres in Europe and Russia. Eligible individuals had a diagnosis of epilepsy and received Perampanel primary or secondary monotherapy as routine clinical care. The primary endpoint was proportion of individuals remaining on Perampanel monotherapy, after conversion from Perampanel adjunctive treatment, at 3, 6, 12, 18 and 24 months (retention rate). Results Sixty individuals were in the safety set (female, 63%; white, 97%; aged 18 to Conclusions In this small retrospective study of individuals who received Perampanel monotherapy, the majority maintained monotherapy. Perampanel monotherapy may be an achievable option in some people with epilepsy.

Betsy Williams - One of the best experts on this subject based on the ideXlab platform.

  • 055 effect of common concomitant antiepileptic drugs during adjunctive treatment with Perampanel post hoc analysis from the open label extension of a phase iii study in patients with idiopathic generalised epilepsy
    Journal of Neurology Neurosurgery and Psychiatry, 2018
    Co-Authors: Terence J Obrien, Francesco Bibbiani, Anna Patten, Antonio Laurenza, Betsy Williams
    Abstract:

    Introduction Perampanel is approved for adjunctive treatment of partial seizures, with or without secondarily generalised seizures, and primary generalised tonic-clonic (PGTC) seizures in epilepsy patients aged ≥12 years. Perampanel is also approved for monotherapy use for partial seizures in the US. This post hoc analysis assessed the effects of the most common concomitant Baseline antiepileptic drugs (AEDs) on discontinuation rates and treatment-emergent adverse event (TEAE) incidence during adjunctive treatment with Perampanel in patients (aged ≥12 years) with idiopathic generalised epilepsy (IGE) and PGTC seizures in the open-label extension (OLEx) Phase of Study 332 (NCT02307578). Methods Patients completing the double-blind study could receive Perampanel (≤12 mg/day) during the OLEx (6 week blinded Conversion Period;≤136 weeks’ Maintenance). Here, we report results for Perampanel >4–8 mg/day and >8–12 mg/day. Results Most common concomitant Baseline AEDs were valproic acid (n=55), lamotrigine (n=53), levetiracetam (n=37), topiramate (n=21) and zonisamide (n=12); patients may have received >1 of these Baseline AEDs. The most common reasons for discontinuing were adverse event(s) (AE), ‘other’ and patient choice. Lamotrigine: patient choice, n=6/34 (>4–8 mg/day); AE/‘other’, both n=3/19 (>8–12 mg/day). Levetiracetam: patient choice, n=5/27 (>4–8 mg/day); AE, n=2/10 (>8–12 mg/day). Topiramate: ‘other’, n=3/15 (>4–8 mg/day); AE/‘other’, both n=1/6 (>8–12 mg/day). Valproic acid: patient choice, n=6/38 (>4–8 mg/day); ‘other’, n=4/17 (>8–12 mg/day). Zonisamide: patient choice/‘other’, both n=2/10 (>4–8 mg/day); no discontinuations (>8–12 mg/day). Patient-reported TEAEs ranged from: 88.2% (lamotrigine) to 93.3% (topiramate) for Perampanel >4–8 mg/day, and 70.6% (valproic acid) to 100.0% (topiramate and zonisamide) for Perampanel >8–12 mg/day. The most common TEAE was dizziness. Conclusion In this post hoc analysis, primary reasons for discontinuation and TEAE incidence differed between the most common Baseline AED subgroups and Perampanel dose range, although TEAE types were similar. These data provide additional information on the safety of adjunctive Perampanel in patients with IGE. Study support Eisai Inc.

  • analysis of falls in patients with epilepsy enrolled in the Perampanel phase iii randomized double blind studies
    Epilepsia, 2017
    Co-Authors: Ilo E Leppik, Francesco Bibbiani, Anna Patten, Betsy Williams, Haichen Yang, Sharon Zhou, Randi Fain, Antonio Laurenza
    Abstract:

    SummaryObjective To analyze occurrence of falls among patients with partial seizures, with/without secondarily generalized seizures (SGS), and primary generalized tonic–clonic seizures (PGTCS) in the Perampanel phase III clinical studies. Methods Studies 304, 305, and 306 randomized subjects (≥12 years) with drug-resistant partial seizures (with/without SGS) to Perampanel 2, 4, 8, or 12 mg or placebo for double-blind treatment. The adverse event (AE) of falls was analyzed in the Safety Analysis Set (N = 1480). Study 332 randomized subjects aged ≥12 years with a diagnosis of PGTCS into Perampanel 8 mg or placebo groups for double-blind treatment. In a systematic review of reported falls in the study 332 Safety Analysis Set (N = 163), falls were queried to establish whether each was seizure related; subjects with falls resulting from a seizure were not included in this analysis. Results For studies 304/305/306, treatment-emergent falls occurred in 5.1% Perampanel-treated versus 3.4% placebo-treated subjects with partial seizures. Exposure-adjusted rate for falls (falls/subject-month of exposure) was greater for total Perampanel than for placebo (0.0175 vs. 0.0093) and was dose related for those receiving Perampanel. In subjects with SGS, incidence of treatment-emergent falls was 4.3% in Perampanel and 4.0% in placebo groups. Exposure-adjusted rates were 0.0169 and 0.0097 falls per subject-month of exposure in Perampanel and placebo, respectively. For study 332, 2.5% Perampanel-treated and 1.2% placebo-treated subjects with PGTCS had treatment-emergent falls that were not part of a seizure. Exposure-adjusted rates were 0.0169 and 0.0032 falls per subject-month of exposure in Perampanel and placebo, respectively. Significance Results of the Perampanel studies suggest that patients with epilepsy should be monitored due to the common risk of falls.

  • PSYCHIATRIC/BEHAVIOURAL EVENTS WITH Perampanel TREATMENT FOR PGTCS
    Journal of Neurology Neurosurgery & Psychiatry, 2016
    Co-Authors: Cindy Dobrinsky, Anna Patten, Betsy Williams, Antonio Laurenza, Haichen Yang, Alan B. Ettinger, William Rosenfeld, Francesco Bibbiani
    Abstract:

    Purpose To review psychiatric and behavioural events in a study conducted to evaluate the efficacy and safety of adjunctive Perampanel in patients with uncontrolled primary generalised tonic-clonic seizures (PGTCS). Method Following baseline (4 or 8 weeks), patients aged ≥12 years were randomised to double-blind treatment with Perampanel or placebo (titration 4 weeks; maintenance 13 weeks; maximum dose 8 mg). Treatment-emergent adverse events (TEAEs) were evaluated using MedDRA search terms for psychiatric disorders and MedDRA SMQs for hostility/aggression-related events. Results In the Safety Analysis Set (Perampanel n=81; placebo n=82), psychiatric TEAEs occurred in 20 (24.7%) Perampanel- and 16 (19.5%) placebo-treated patients. Most TEAEs were of mild or moderate intensity. Frequency of TEAEs related to hostility/aggression was 18.5% for Perampanel and 4.9% for placebo, largely due to a higher rate of irritability with Perampanel (11.1%) versus placebo (2.4%). Incidences of serious adverse events and discontinuations due to TEAEs related to hostility/aggression for Perampanel versus placebo were 1.2% versus 0% and 3.7% versus 1.2%, respectively. Conclusion Consistent with results from Phase III trials in partial epilepsy, hostility/aggression-related TEAEs occurred at a higher rate in Perampanel-treated patients with PGTCS than in those treated with placebo, driven mainly by irritability. Supported by Eisai Inc.

  • Perampanel TREATMENT FOR GENERALISED TONIC-CLONIC SEIZURES
    Journal of Neurology Neurosurgery & Psychiatry, 2016
    Co-Authors: Terence J. O'brien, Francesco Bibbiani, Anna Patten, Betsy Williams, Haichen Yang, Antonio Laurenza
    Abstract:

    Purpose A post hoc analysis evaluated the efficacy and tolerability of Perampanel across four Phase III studies in patients with secondarily generalised (SG) or primary generalised tonic-clonic (PGTC) seizures. Method All studies involved patients aged ≥12 years. Studies 304 (n=388) and 305 (n=386) evaluated Perampanel 8 or 12 mg/day or placebo. Study 306 (n=706) evaluated Perampanel 2, 4, or 8 mg/day or placebo. These studies had a 19-week double-blind phase (6-week titration; 13-week maintenance). Study 332 (n=164) evaluated Perampanel up to 8 mg/day or placebo (17-week double-blind phase; 4-week titration, 13-week maintenance). Full Analysis Set (FAS) included patients who had SG or PGTC seizures and received Perampanel 8 mg/day. Results FAS included 492 patients (mean age 31.7 years). Compared with placebo, Perampanel conferred a greater median percent reduction in PGTC/SG seizure frequency per 28 days (−24.6% vs. −65.5%; p Conclusion Perampanel reduced generalised tonic-clonic seizure frequency, whether primary or SG, and was well tolerated. Funded by Eisai Inc.

  • relationship between Perampanel exposure seizure outcomes and treatment emergent adverse events teaes in patients with primary generalized tonic clonic seizures pgtcs a randomized double blind db phase iii study p2 024
    Neurology, 2016
    Co-Authors: Gregory L Krauss, Francesco Bibbiani, Anna Patten, Betsy Williams, Haichen Yang, Barry E Gidal, Robert T Wechsler, Ziad Hussein
    Abstract:

    Objective: To characterize relationships between Perampanel exposure, PGTCS outcomes, and TEAEs in patients with uncontrolled PGTCS. Background: PER, a non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of partial seizures with or without secondarily generalized seizures and for PGTCS in patients with epilepsy aged ≥12 years. Design/Methods: Enrolled patients were aged ≥12yrs with uncontrolled PGTCS receiving 1-3 concomitant antiepileptic drugs (AEDs). Following baseline (4 or 8wks), patients were randomized into Perampanel or placebo groups for DB treatment (Titration, 4wks; Maintenance, 13wks), with an 8mg maximum dose. Primary endpoints were percent change in PGTC seizure frequency/28days and 50[percnt] responder rate. Pharmacokinetic/pharmacodynamics (PK/PD) models were used to describe relationships between Perampanel exposure and seizure outcomes, and neuropsychiatric TEAEs of special interest (e.g., hostility/aggression-related TEAEs using Standardized MedDRA Queries). Results: PK/PD analysis included data from patients receiving Perampanel (N=72) and placebo (N=77). Perampanel reduced PGTCS frequency in a log-linear exposure relationship with no time effect versus placebo. During Maintenance, the model predicted PGTCS frequency reductions of Perampanel 62.3[percnt] versus placebo 31.7[percnt] for a typical male on non-enzyme-inducing AEDs (non-EIAEDs). Concomitant EIAED treatment reduced probability of responding due to lower Perampanel exposure [Perampanel 8mg/day: non-EIAEDs=0.85, concomitant carbamazepine (EIAED)=0.80; placebo=0.39]. In the exposure-safety dataset (Perampanel, n=73; placebo, n=78), median Perampanel exposure was higher in patients experiencing hostility/aggression-related TEAEs (n=12) than in those without, although concentrations overlapped substantially. High variability in event probability and low patient numbers prevented formal modeling of the exposure-adverse event incidence relationship. Conclusions: Response rate increased, and responder probability was predicted to increase, with increased Perampanel exposure. Perampanel exposure was reduced by concomitant EIAEDs. Median Perampanel exposure was higher in patients experiencing hostility/aggression-related TEAEs versus those without, although concentrations overlapped substantially. Ref:1Piedad.CNS Drugs2012;26:319-35 Support: Eisai Inc. Disclosure: Dr. Krauss has nothing to disclose. Dr. Wechsler has received personal compensation for activities with Cyberonics, Eisai, Gerson Lehrman Group Inc., Lundbeck, Sunovion, UCB Pharma, and Upsher-Smith. Dr. Bibbiani has received personal compensation for activities with Eisai Inc. as an employee. Dr. Patten has received personal compensation for activities with Eisai Ltd. Dr. Williams has received personal compensation for activities with Eisai Inc. as an employee. Dr. Yang has received personal compensation for activities with Eisai Inc. as an employee. Dr. Gidal has received personal compensation for activities with Upsher-Smith. Dr. Hussein has received personal compensation for activities with Eisai Ltd. as an employee.

Jim Ferry - One of the best experts on this subject based on the ideXlab platform.

  • Changes in Perampanel levels during de-induction: Simulations following carbamazepine discontinuation.
    Acta neurologica Scandinavica, 2020
    Co-Authors: Edgar Schuck, Jim Ferry, Barry E Gidal, Ziad Hussein
    Abstract:

    Objective To evaluate the time course of changes in Perampanel levels when co-administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model. Methods The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down-titration (75 mg twice daily [bid]/wk) of co-administered carbamazepine 300 mg bid on the PK of Perampanel once daily (qd). Perampanel dose tapering (8-4 mg) and up-titration (2-6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in Perampanel plasma concentrations. Results The PBPK model accurately reproduced Perampanel plasma concentration-time profiles from clinical studies in single- and multiple-dose regimen simulations, including multiple-dose carbamazepine co-administration. The time course of return to pre-induced Perampanel levels occurred more slowly following carbamazepine down-titration (~48 days after first down-titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8-4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady-state concentrations, which returned to the levels observed during carbamazepine co-administration in ~15 days from the time of carbamazepine discontinuation. When Perampanel was up-titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down-titrated weekly (~45 days) vs abrupt discontinuation (~24 days). Conclusion This PBPK model simulated and predicted optimal Perampanel dose tapering and up-titration schedules for maintaining Perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from Perampanel polytherapy with concomitant enzyme-inducing anti-seizure medications to monotherapy.

  • Potential protein-binding displacement interactions with Perampanel: An in vitro analysis.
    Epilepsy research, 2018
    Co-Authors: Barry E Gidal, Antonio Laurenza, Jim Ferry, Takashi Ueno
    Abstract:

    Abstract Plasma protein binding and effects on volume of distribution and pharmacologically active, circulating-drug concentrations are complex issues. Protein-binding displacement often underlies drug–drug interactions. Perampanel is a once-daily oral anti-seizure drug for focal seizures and primary generalized tonic-clonic seizures. Perampanel is also indicated for monotherapy use for focal seizures in the United States. Perampanel is extensively but slowly metabolized via CYP3A4. Its elimination t½ is about 100 h, and it displays substantial plasma protein binding (>95%). Here, we examine Perampanel’s potential to displace highly bound anti-seizure drugs and the ability of warfarin, a standard highly protein-bound drug, to displace Perampanel. Protein binding of Perampanel, phenytoin, valproate, and warfarin was assessed using equilibrium dialysis. Plasma samples containing each compound were dialyzed against phosphate buffered saline. For phenytoin, valproate, and warfarin, plasma samples were also dialyzed in the presence of Perampanel. After 24 h equilibrium dialysis, amounts of test compounds were analyzed to calculate plasma protein binding. At clinically relevant concentrations, Perampanel did not displace other highly bound drugs or vice versa. Protein-binding displacement may confound therapeutic drug monitoring of extensively protein-bound medications. Without empirical data, clinicians might be concerned that addition of Perampanel could alter unbound concentrations of other medications, resulting in adverse effects. Our data indicate Perampanel has low potential for drug interactions resulting from protein-binding displacement.

  • pharmacokinetic pharmacodynamic analysis of adjunctive Perampanel in subjects with partial onset seizures
    Acta Neurologica Scandinavica, 2018
    Co-Authors: O. Takenaka, Jim Ferry, K. Saeki, Antonio Laurenza
    Abstract:

    OBJECTIVES Explore Perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis. MATERIALS & METHODS Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive Perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between Perampanel exposure and 28-day average seizure frequency and responder probability. RESULTS Pooled Perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting Perampanel PK, estimated Perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced Perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered Perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing Perampanel exposure; concomitant CYP3A-inducing AEDs lowered Perampanel exposure but did not impact the slope for responder probability. CONCLUSIONS These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

  • Pharmacokinetic/pharmacodynamic analysis of adjunctive Perampanel in subjects with partial‐onset seizures
    Acta neurologica Scandinavica, 2017
    Co-Authors: O. Takenaka, Jim Ferry, K. Saeki, Antonio Laurenza
    Abstract:

    OBJECTIVES Explore Perampanel pharmacokinetics (PK) in all subjects (aged ≥12 years) vs adolescents (aged ≥12 to ≤17 years) with partial-onset seizures (POS) and identify factors explaining between-subject variability in efficacy using a population PK/pharmacodynamic (PD) analysis. MATERIALS & METHODS Population PK analysis was performed using nonlinear mixed-effect modeling with data from phase II/III randomized, double-blind, placebo-controlled studies of adjunctive Perampanel in POS. Perampanel exposure was predicted for all subjects and adolescents. Population PK/PD analyses were performed using data from phase III studies to explore the relationship between Perampanel exposure and 28-day average seizure frequency and responder probability. RESULTS Pooled Perampanel PK data from 1318 subjects were described by a one-compartment disposition model. In the absence of antiepileptic drugs (AEDs) affecting Perampanel PK, estimated Perampanel apparent clearance (CL/F) was 0.668 L/h (all subjects) and 0.682 L/h (adolescent subjects). Co-administration of carbamazepine and oxcarbazepine/phenytoin reduced Perampanel exposure. Gender, Asian race (excluding Japanese or Chinese), and increasing alanine aminotransferase lowered Perampanel CL/F, but differences were small and not considered clinically relevant. Adolescent outcomes were similar to the total population. Based on PK/PD data from 1748 subjects, percent reduction in 28-day average seizure frequency from baseline and responder probability increased with increasing Perampanel exposure; concomitant CYP3A-inducing AEDs lowered Perampanel exposure but did not impact the slope for responder probability. CONCLUSIONS These results are consistent with previous analyses but expand on these through inclusion of a larger number of patients from different ethnic groups, and demonstrate that outcomes were similar between adults and adolescents.

  • Effect of Enzyme Inhibition on Perampanel Pharmacokinetics: Why Study Design Matters
    Epilepsy research, 2017
    Co-Authors: Barry E Gidal, Antonio Laurenza, Haichen Yang, Edgar Schuck, Rama Maganti, David Verbel, Jim Ferry
    Abstract:

    Abstract Objectives Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that Perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t 1/2 ) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions—enzyme inhibition or induction—and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining Perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. Methods A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of Perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg Perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the Perampanel dose. Pharmacokinetic parameters of Perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp ® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of Perampanel in the presence or absence of concomitant ketoconazole. Results Single oral doses of 1mg Perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum Perampanel plasma concentration (C max ) and time to C max showed no apparent differences when Perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in Perampanel AUC ( P 0.001). This increase, although statistically significant, was a 2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of Perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. Conclusions Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as Perampanel that have a long t 1/2 . Although a negligible effect on Perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and Perampanel ( 1/2 of Perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase Perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.