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 (t1/2) 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 (Cmax) and time to Cmax 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<2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>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 t1/2. 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 (<3 times the t1/2 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.
journal_name
Epilepsy Resjournal_title
Epilepsy researchauthors
Gidal BE,Maganti R,Laurenza A,Yang H,Verbel DA,Schuck E,Ferry Jdoi
10.1016/j.eplepsyres.2017.04.018subject
Has Abstractpub_date
2017-08-01 00:00:00pages
41-48eissn
0920-1211issn
1872-6844pii
S0920-1211(17)30256-5journal_volume
134pub_type
杂志文章,随机对照试验abstract::The motivational consequences of kindling were examined in the conditioned place preference paradigm. In a distinctive environment, rats received stimulation of the amygdala that triggered afterdischarge (AD) alone or AD and generalized seizures. After 4 conditioning trials, preference for the conditioning environment...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(92)90051-t
更新日期:1992-12-01 00:00:00
abstract:PURPOSE:To compare and validate the gradient magnetic-field topography (GMFT) method of current source localization for understanding epileptic zones against equivalent current dipole (ECD) and intracranial video-EEG (IVEEG) data in patients with intractable neocortical epilepsy. METHODS:We used retrospective data fro...
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abstract:PURPOSE:To assess subjective seizure anticipation in patients with focal and generalized epilepsy. METHODS:Five hundred consecutively recruited out-patients (251 male, 249 female, mean age 38.1 year) from three German tertiary epilepsy referral centres filled out questionnaires regarding subjective anticipation of sei...
journal_title:Epilepsy research
pub_type: 杂志文章,多中心研究
doi:10.1016/j.eplepsyres.2006.02.001
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pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2008.11.004
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abstract:PURPOSE:The intracarotid amytal test is commonly used as a predictor of memory dysfunctioning after anterior temporal lobe resection (ATL) for intractable epilepsy. Asymmetry in memory scores can provide focus lateralizing information. In this study the predictive value of a set of Wada test parameters was analyzed, in...
journal_title:Epilepsy research
pub_type: 临床试验,杂志文章
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更新日期:2000-05-01 00:00:00
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pub_type: 杂志文章,meta分析,评审
doi:10.1016/j.eplepsyres.2014.09.030
更新日期:2014-12-01 00:00:00
abstract::Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assesse...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2012.11.004
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abstract:INTRODUCTION:Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy syndrome. Under appropriate antiepileptic drugs (AED) up to 85% of patients become seizure-free, but many may have a relapse after AED withdrawal. METHODS:We retrospectively studied 242 patients with JME at the Department of Neurology, Me...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2014.09.008
更新日期:2014-12-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章,评审
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2018.06.001
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abstract::Twenty-one children (11 boys, 10 girls) suffering from visual seizures were studied. The visual seizures manifested as loss of vision, flickering light, blurring or figurative hallucinations. Ictal EEGs during visual seizures were recorded in 4 cases; the ictal discharges all originated in the occipital area. Visual s...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(87)90032-5
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abstract::To clarify the mechanisms of the antiepileptic activity of phenytoin (PHI), the effects of PHT on extracellular and total levels of monoamines (dopamine and serotonin), in rat striatum and hippocampus were studied. The plasma concentrations of PHT associated with therapeutic activity did not affect striatal and hippoc...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/s0920-1211(97)00043-0
更新日期:1997-09-01 00:00:00
abstract:PURPOSE:We investigated long term prognosis of Lennox-Gastaut syndrome (LGS) with active application of recent advanced treatment modalities such as ketogenic diet (KD) or epilepsy surgery (ES). METHODS:We retrospectively evaluated 68 patients with LGS, aged 18-35 years. We assessed seizure outcomes for a range of the...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2014.11.004
更新日期:2015-02-01 00:00:00
abstract::The intracarotid amobarbital procedure (IAP) was attempted in 22 pediatric epilepsy surgery candidates, ages 5-12 years old. With extra pre-test teaching and emotional preparation, adjusted amobarbital dosage for younger patients, and simplified test items tailored to the child's abilities, language and memory testing...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(93)90061-b
更新日期:1993-07-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2004.04.005
更新日期:2004-04-01 00:00:00
abstract::The 5-hydroxytryptamine-1A (5-HT1A) receptors are known to be involved in the inhibition of seizures in epilepsy. Moreover, studies propose a role for the 5-HT1A receptor in memory function; it is believed that the higher density of this receptor in the hippocampus plays an important role in its regulation. Positron e...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2014.09.013
更新日期:2014-12-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(89)90042-9
更新日期:1989-03-01 00:00:00
abstract::The present study used Nissl stains and glutamate decarboxylase immunoreactivity (GAD-IR) to quantify the acute and chronic toxicity of kainic acid (KA) on focal and remote hippocampal principal neurons (i.e., pyramidal and granule cells) and on putative inhibitory neurons (GAD-IR or GABAergic) following intrahippocam...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(90)90063-2
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abstract::Seizures induced by the convulsant methionine sulfoximine (MSO) resemble human "grand mal" epilepsy, and brain glutamine synthetase is inhibited. We recently selected two inbred lines of mice: sensitive to MSO (MSO-Fast) and resistant (MSO-Slow). In the present study, the selection pressure was increased and consangui...
journal_title:Epilepsy research
pub_type: 杂志文章
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2006.11.005
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journal_title:Epilepsy research
pub_type: 杂志文章
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更新日期:2021-01-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2009.12.005
更新日期:2010-05-01 00:00:00
abstract:PURPOSE:We performed a retrospective study to investigate seizure, EEG, social and cognitive outcome in adult LGS subjects. METHODS:We retrospectively evaluated 27 LGS patients aged 40-59 years. We assessed in particular the evolution of different seizure types and EEG findings, as well as cognitive and social outcome...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2010.01.012
更新日期:2010-05-01 00:00:00
abstract::Interactions of subclinical epileptiform EEG discharges and cognitive functioning were studied in 91 patients with epilepsy, under video monitoring, to exclude overt clinical ictal phenomena during the investigations. A short-term memory test was presented as an engaging television game, in two versions, using spatial...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(87)90031-3
更新日期:1987-07-01 00:00:00
abstract::The subjects were 106 SMIDS with epilepsy. They were classified into four epileptic syndromes: (1) SE-MISF (34.0%), (2) SGE (25.5%), (3) SLRE (20.7%), and (4) epileptic discharge-free patients (EDFP) (19.8%). Clinical electroencephalographic studies elucidated the following result: (1) The seizure disappearance rate w...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2007.09.006
更新日期:2007-12-01 00:00:00
abstract:BACKGROUND:Diffusion tensor tractography of the anterior extent of the optic radiation - Meyer's loop - prior to temporal lobe resection (TLR) may reduce the risk for postoperative visual field defect. Currently there is no standardized way to perform tractography. OBJECTIVE:To visualize Meyer's loop using determinist...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2014.01.017
更新日期:2014-03-01 00:00:00
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journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2011.05.015
更新日期:2011-09-01 00:00:00
abstract:PURPOSE:To identify clinical risk factors for Dravet syndrome (DS) in a population of children with status epilepticus (SE). MATERIAL AND METHODS:Children aged between 1 month and 16 years with at least one episode of SE were referred from 6 pediatric neurology centers in Switzerland. SE was defined as a clinical seiz...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2014.02.019
更新日期:2014-05-01 00:00:00
abstract::Polyamine (tissue) concentrations have been studied in hippocampus and temporal neocortex from patients with temporal lobe epilepsy. Depth electrode recordings demonstrated hippocampal origin of the seizures, the temporal neocortex being involved during the discharge propagation. Neuropathological examination of excis...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/0920-1211(92)90035-r
更新日期:1992-07-01 00:00:00
abstract:PURPOSE:To try to prove in patients with refractory symptomatic epilepsy due to early brain injury involving thalamus and complicated by CSWS the effects of the isolation of the injured hemisphere, performed with functional hemisperectomy, on epilepsy, namely on CSWS. METHODS:Full clinical follow-up before and after s...
journal_title:Epilepsy research
pub_type: 杂志文章
doi:10.1016/j.eplepsyres.2009.09.014
更新日期:2009-12-01 00:00:00