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Perampanel for epilepsy with partial-onset seizures: a pharmacokinetic and pharmacodynamic evaluation a

Andreas Schulze-Bonhage MD, PhD Professor a

University Hospital Freiburg, Epilepsy Center, Breisacher Str. 64, D-79106 Freiburg, Germany, Europe +49 761 270 53660; +49 761 270 50030; Published online: 29 Jun 2015.

Click for updates To cite this article: Andreas Schulze-Bonhage MD, PhD Professor (2015) Perampanel for epilepsy with partial-onset seizures: a pharmacokinetic and pharmacodynamic evaluation, Expert Opinion on Drug Metabolism & Toxicology, 11:8, 1329-1337 To link to this article: http://dx.doi.org/10.1517/17425255.2015.1061504

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Drug Evaluation

1.

Introduction

2.

Pharmacodynamics

3.

Pharmacokinetics and metabolism

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Perampanel for epilepsy with partial-onset seizures: a pharmacokinetic and pharmacodynamic evaluation

4.

Conclusion

5.

Expert opinion

Andreas Schulze-Bonhage University Hospital Freiburg, Epilepsy Center, Breisacher Str. 64, D-79106 Freiburg, Germany, Europe

Introduction: Epilepsies are among the most common diseases of the CNS. As available antiepileptic drugs do not successfully control seizures in one-third of these patients, the development of drugs with new mechanisms of action is an urgent requirement. Areas covered: Preclinical and clinical data of the recently released antiepileptic drug perampanel are reviewed based on search in medical databases with special reference to its mechanism of action and to its pharmacokinetic properties relevant for clinical treatment. Pharmacodynamically, perampanel is a noncompetitive AMPA-receptor antagonist exerting its antiepileptic properties by modulating glutamatergic synaptic excitation. Pharmacokinetically, perampanel is characterized by a short Tmax but slow hepatic metabolism and a mean plasma half-life of 105 h, allowing for once-daily dosing. Perampanel has shown antiepileptic properties in several animal models of seizures and epilepsy, and in clinical studies significantly reducing partial-onset seizures in a dose range from 4 to 12 mg/day both in blinded short-term and in open-label long-term extension trials even in highly pharmacoresistant patients. Aside from adverse effects of dizziness and somnolence, neuropsychiatric disturbances have been reported in patient subgroups, making careful clinical monitoring during uptitration recommendable. Expert opinion: The use of perampanel focusing on control of abnormal synaptic excitation profits from favorable pharmacokinetics and from proven efficacy and overall good tolerability also in patient populations nonresponsive to treatment with previously available antiepileptic drugs. Keywords: AMPA receptor, antiepileptic drug, epilepsy, perampanel, pharmacodynamics, pharmacokinetics Expert Opin. Drug Metab. Toxicol. (2015) 11(8):1329-1337

1.

Introduction

Epilepsy is one of the most frequent chronic diseases of the brain, affecting ~ 50 million patients worldwide [1]. Whereas epileptic seizures can be well controlled in two-third of patients, for one-third antiepileptic drugs (AEDs) available do not provide adequate efficacy. There is thus a need for the development of new therapeutic strategies for this considerable patient population. Perampanel (PER) (Box 1) (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2 dihydropyridin-3-yl]benzonitrile hydrate) is latest new AED available for treatment of partialonset seizures. Following a series of second-generation AEDs, which have become available since 1989, it has a new well-defined mechanism of action by selectively modulating excitatory glutamatergic transmission via modulation of the AMPA receptor. So far, AEDs had preferentially modified fast neuronal discharges via 10.1517/17425255.2015.1061504 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary. Perampanel Approved (Phase IV) For add-on treatment of epilepsy with partial-onset seizures from age ‡ 12 (US and EU) Pharmacological description/ Non-competitive AMPA mechanism of action receptor antagonist Route of administration Oral Chemical structure 5¢-(2-Cyanphenyl)-1¢-phenyl-2, 3¢-bipyridinyl-6¢(1¢H)-on Pivotal trials NCT00699972, NCT00699582, NCT 00700310

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Name Phase Indication

effects on sodium channels (oxcarbazepine, eslicarbazepine, lacosamide), presynaptic release of neurotransmitters (levetiracetam, gabapentin and pregabalin) and inhibitory synaptic transmission (vigabatrin, tiagabine). Anti-glutamatergic effects contribute to the antiepileptic effects of felbamate (NMDA subreceptor) [2,3], topiramate (kainate subreceptor) [4] and zonisamide [5], yet PER is the first drug specifically designed to modulate AMPA receptors of glutamatergic transmission. Despite the high number of second-generation AEDs available so far, complete seizure control has been achieved only in small additional subgroups treated in regulatory and in prospective long-term studies. The introduction of new mechanisms of action in the pharmacological treatment of epilepsies is thus highly desirable to address the so far unsolved problem of pharmacoresistance in about one-third of patients with partial-onset seizures and to open up new strategies for rational polytherapy. Here, a review on the pharmacodynamics and pharmacokinetics of PER is given, which has been shown in three randomized controlled trials (NCT00699972, NCT 00699582 and NCT 00700310) to be effective in reducing the seizure frequency in patients with so far pharmacoresistant epilepsies [6-8]. Pharmacodynamics and pharmacokinetics of PER are described in detail (cf. Table 1, Figure 1), based on publications and on materials available from FDA and EMA. This pharmacological profile is given in special consideration of its clinical consequences for titration and monitoring of this new AED. 2.

Pharmacodynamics

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Efficacy in animal models To study their antiepileptic properties, AMPA receptor antagonists have been tested in a number of experimental epilepsy models [20,22-27]. PER suppressed seizures in acute models of generalized seizures (maximal electroshock and PTZ model in mice), and was efficacious against seizures with partial onset (audiogenic seizures in DBA/2 mice, 6 Hz seizure model in mice) [23]. In addition, PER showed effects in chronic models 2.2

AMPA receptors As part of the glutamatergic transmission system, AMPA receptors are widely distributed over all neocortical and archicortical brain areas [9] with specific enrichment in glutamatergic synapses [10]. They consist of variable combinations of four subunits (GluA1 -- 4) with regional, timely and activity2.1

dependent differences in expression and stability in synaptic membranes [9,10]. The vast majority of AMPA receptor tetramers expressed in adulthood contain GluA2 subunits and are permeable to Na+ (and K+) ions only, with opening leading to postsynaptic depolarization; GluA2-lacking receptors are also Ca2+-permeable with corresponding higher channel conductance and additional postsynaptic activation cascades [11]. Channel opening occurs when at least two agonist binding sites are occupied [3,11]. Membrane depolarization by activation of AMPA receptors is frequently a precondition to activation of NMDA receptors by removal of Zn2+ blockade. It has been long established that calcium influx via NMDA receptors triggers cascades leading to long-term potentiation and depression. AMPA receptor expression is modulated activity-dependent, with increased AMPA receptor numbers in potentiated and lowered numbers in depressed synapses [10]. Glutamatergic transmission plays a key role not only in physiological excitatory transmission but also particularly in the generation of epileptic discharges. Both, NMDA and non-NMDA subreceptors of glutamate (AMPA and kainate receptors) are key constituents to trigger paroxysmal epileptic discharges and to propagate epileptic activity to synaptically connected neuronal populations. In vitro studies showed that blockade of non-NMDA glutamate receptors reduces or abolishes epileptiform discharges, for example, in hippocampal slices [12,13] by blocking the synchronization and initiation of paroxysmal depolarization of pyramidal neurons. Beyond their role of initiation and synchronization of epileptic discharges, glutamatergic transmission plays a key role in excitotoxic sequelae of epileptic activity on the brain [14,15]. Modulation of glutamate subreceptors thus is an interesting target in the treatment of epilepsy, with possible roles both in treating seizures and in preventing disease progression [16]. Although NDMA receptor antagonists have shown good antiepileptic efficacy [17], they were associated with major behavioral side effects encompassing motor stereotypes like head weaving/nodding and circling in rats [18] and concentration deficits, sedation, disorientation and confusion, depression and impairment of motor coordination, dizziness and diplopia in humans [19]. PER (Figure 2) is an allosteric inhibitor of AMPA receptors with high selectivity for receptor binding to AMPA versus NMDA receptors [20]. The exact site or receptor binding and specific binding properties to different receptor compositions are not known so far [21].

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Perampanel

Table 1. Key pharmacokinetic characteristics. Route of administration Formulation Dosages Bioavailability Protein binding Tmax T½ Time to steady state Metabolization Effect of co-medication on PER metabolization

Oral Film-coated tablets 2, 4, 6, 8, 10 and 12 mg 100% 95% (albumin > a1-glycoprotein, globulins) 0.5 -- 2 h 105 (53 -- 136) h 3 weeks CYP3A4, CYP3A5 > glucuronidation Enzyme inductors plasma levels CBZ -67%; PHT,OXC -50%; TPM -20% Enzyme inhibitors plasma levels OXC-clearance --26%; Levonorgestrel levels -40% Feces (70%), Urine (30%)

Effect of PER on other drugs Elimination

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PER: Perampanel.

Oxcarbazepine Pregabalin Levetiracetam Gabapentin 10-OH-carbazepine Eslicarbazepine-Acetate Valproate Phenytoin Topiramate Lamotrigine Felbamate Ethosuximide Carbamazepine Zonisamide Phenobarbitone Perampanel 0

10 20 30 40 50 60 70 80 90 100 110 120 130 140

Figure 1. Plasma half-time is shown of antiepileptic drugs (range in healthy volunteers). Data taken from [49-52].

of epilepsy; in the amygdala kindling model in rats, afterdischarge duration, seizure duration and severity were reduced [24], whereas effects of AMPA antagonists in absence models of epilepsy were inconsistent [20,25,26]. In slices from human epileptic cortex, PER reduced amplitudes of channel openings and average firing rate after application of picrotoxin [22]. Preclinical data furthermore suggest that co-application of PER with AEDs having different mechanisms of action can lead to additive or potentially synergistic effects. In the 6Hz electroshock model, this was shown in combinations of PER

with carbamazepine, phenytoin and valproate, in the amygdala kindling model in combinations of PER with carbamazepine, lamotrigine, levetiracetam and valproate [20]. Clinical efficacy in human epilepsy Clinically, PER has shown efficacy in reducing partial-onset seizures in patients aged ‡12 years in a dosage range from 4 to 12 mg/day. Once-daily intake of PER showed significant reductions in seizure frequency in randomized, controlled, multicenter trials at dosages of 8 and 12 mg/day [6,8], and in dosages of 4 and 8 mg/day [7], whereas a dose of 2 mg/day 2.3

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A. Schulze-Bonhage

Perampanel 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2 dihydropyridin-3-yl)benzonitrile N

N O CN

Licensed for the adjunctive treatment of partial onset seizures with or without secondarily generalization in patients with epilepsy ≥ 12 years of age

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Figure 2. Schematic representation of perampanel.

did not show significant effects in the latter study. In a pooled analysis of these three trials, seizure reduction during the 13-week maintenance period was -23.3% at 4 mg, -28.8% at 8 mg and -27.2% at 12 mg; with placebo, seizure frequency decreased by 12.8% (p < 0.01 for each of these dosages). In two of these studies, responder rates also differed significantly from placebo at dosages of 4 -- 12 mg/day [7,8], whereas in one study this outcome parameter was not met [6]. Whereas efficacy in patients randomized to 8 and 12 mg/ day did not differ in blinded studies, uptitration from 8 to 12 mg in extension studies increased the median reduction in seizure frequency from -32.4 to -44.2% and responder rates from 37.3 to 42.9%, with particular improvement in the control of secondarily generalized seizures [28]. Interestingly, > 90% of patients could be uptitrated to daily doses of 10 or 12 mg, resulting in a mean dose of 10.6 mg/day in this open-label study lasting an average of 1.5 years. Overall, long-term extension studies showed stable responder rates and degrees of seizure reduction [29], without evidence for the development of tolerance to PER. Whereas seizure freedom was achieved only in < 5% of patients during controlled studies, a German multicenter retrospective analysis reported that 15% of patients achieved complete seizure control for a follow-up period of 6 months [30]. Adverse effects of PER treatment Exposition of animal models to PER resulted in motor impairment at dosages only slightly beyond doses which showed antiepileptic efficacy in the rotarod tests [21]. Accordingly, motor impairment was expected also in humans. In randomized, placebo-controlled studies, add-on treatment with PER was dose-dependently associated with common adverse events in the form of dizziness (16.3 -- 42.7 vs 9.0% with placebo), somnolence (9.3 -- 17.6 vs 7.2% with placebo), headache (11.0 -- 13.3 vs 11.3% with placebo, n.s.), fatigue (7.6 -- 12.2 vs 4.8% with placebo), irritability (4.1 -- 11.8 vs 2.9% with placebo), falls (1.7 -- 10.2 vs 3.4% 2.4

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with placebo) and nausea (2.9 -- 7.8 vs 4.5% with placebo) at dosages of 4 -- 12 mg/day [31]; less frequently, ataxia and balance disorders were reported. In these 3-month studies, discontinuation rates under PER treatment ranged from 2.9 to 19.2% at this dose range. Neuropsychiatric side effects were rare: depression 0.6 -- 2.4% (vs 1.6% with placebo), aggression 0.6 -- 3.1% (vs 0.5% with placebo); there was one case of suicidal ideation at 8 mg/day. In long-term extension studies, most frequent side effects remained dizziness, somnolence and headache, but also fatigue, irritability and weight increase were reported in > 10% of patients. In one analysis of extension studies following Phase III trials, considerable psychiatric side effects were reported, consisting of depression, insomnia, aggression and anxiety in ~ 5% of patients. About 3.9% of patients had severe psychiatric adverse events, 42% of whom had a history of previous psychiatric disorders. This incidence of 3.9% severe psychiatric adverse events within 170 weeks needs to be compared with an incidence of 0.9% in the shorter 19-week period under placebo add-on treatment. For some psychiatric symptoms (irritability, aggression and anger), data suggest a higher risk at 12 mg compared to 8 mg/day dose. About 5.5% of patients discontinued PER treatment due to psychiatric side effects. There were marked regional differences in this with North American patients discontinuing twice as frequently compared to epilepsy patients in Europe and Asia, and three times as often as patients from South America [29]. It is interesting that in a long-term extension study of Phase II studies in which patients were on average titrated less rapidly and ended up at lower PER doses (range 2 -- 12 mg/day, only 34% of patients were treated at dosages of 10 or 12 mg/day), the incidence and severity of psychiatric side effect was considerably lower: only irritability (7.2%) and anxiety (5.1%) were among the 26 most common treatmentemergent adverse events, and there no cases of suicidal ideation [32].

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Perampanel

In the extension phase of Phase III studies, weight increase was also three times more frequent in North America compared to Europe [29]. It is of note that the high incidence of weight increase reported in this long-term study (37.8% of patients with > 7% weight increase) was partially related to adolescents (12 -- 18 years of age) in the patient population. So far, there are no reports on unequivocal hypersensitivity reactions [33]. Whereas the types of adverse effects were similar in patients aged ‡ 65 years, incidence of dizziness, fatigue and falls was higher in a subanalysis of Phase III clinical trials [34]. In elderly patients with epilepsy, treatment at minimal effective dosages is thus of particular importance. In one patient, intoxication with an assumed dose of 204 mg was reported to result in dysarthria and tiredness, weakening of reflexes and sopor -- accompanied by EEG slowing, with the patient agitated and disoriented later; symptoms were reversible without gastric lavage [35]. Rash as the most common idiosyncratic reaction to AEDs was observed in 18 of 2627 (0.7%) patients receiving PER compared to 4 of 1320 patients on placebo (0.3%, difference n.s. [33,36]). In addition, so far one more severe but reversible idiosyncratic reaction (drug reaction with eosinophilia and systemic symptoms) was reported in a girl with cerebral saltwasting syndrome [37]. Pharmacodynamic interactions of PER with other drugs

2.5

Co-application of PER with carbamazepine showed increased sedation in healthy volunteers [38], and co-application with levetiracetam in patients in clinical studies showed an increased risk of fatigue [39,40]. Co-ingestion of alcohol with PER showed impaired psychomotor performance in patients already treated with 4 mg/day, which was at least additive to the effects of alcohol [38]. At high dosages (12 mg/day), cognitive side effects with co-ingestion with alcohol were seen particularly regarding frontal lobe functions (working memory and executive functions) [40]; so far, standardized neuropsychological data are not available in epilepsy patients. 3.

Pharmacokinetics and metabolism

Absorption of PER with oral application With oral application, PER is completely and rapidly absorbed from the gastrointestinal tract [38]. Bioavailability has been shown to be 100% [38,39], without relevant firstpass metabolism. In healthy volunteers, linearity of dose and plasma concentrations has been demonstrated for a wide range of doses (0.2 -- 12 mg), covering the clinical use [38]. In clinical trials with add-on treatment of PER, this linear relationship was confirmed in epilepsy patients [41]. There is no evidence of auto-induction or auto-inhibition when analyzing dose--plasma concentration relations over time. Absorption of PER is rapid, with a median Tmax of 1 h (range 0.5 -- 2 h in epilepsy patients) [40]. When PER is taken 3.1

with food, Tmax can be delayed by 2 -- 3 h and reduced by 28 -- 40%; in contrast, the total amount of drug absorbed (AUC) is not affected by simultaneous food consumption [38]. Intake of PER with food may thus offer advantages in case that adverse effects-related peak plasma concentrations play a role. Distribution of PER PER has a high volume of apparent distribution (1.1 l/kg) when applied in single dosages [38]. In vitro studies show that 95% of PER in plasma is bound to proteins (albumin and a-1-acid glycoprotein), with a free fraction of < 5% [38]. In rat studies, PER was shown to cross the placenta with fetal rat blood levels of 34 -- 48% of maternal levels, and brain levels of 59 -- 88% of the maternal rat [42]. There are so far no published data on adverse PER effects on human offspring, but in rats, PER at doses starting from 1 mg/kg/day (assumed to be similar to 8 mg/kg/day in humans) lead to embryotoxic effects on the intestine, and at higher doses reduced fetal body weight and lethality were observed [38]. PER is also excreted in the breast milk; in lactating rats, levels reached the 2.5- to 3.9-fold concentrations of maternal plasma [39]. PER readily crosses the blood--brain barrier and is not subject to blood--brain multidrug efflux transporters, such as Pg-P, which have been claimed to play a role in the development of pharmacoresistance [21,39,43]. There are a few tissues in which PER can be shown for periods of years after single dose exposition (monkey ocular tissues, rat eyeball and aorta); in the brain, however, radiolabeled PER falls below detection limits within 24 h [39]. 3.2

Metabolism of PER About 90% of PER are metabolized in the liver by ring oxidation via CYP enzymes 3A4 and 3A5 and by subsequent glucuronidation [39,40,42]. The diverse metabolites of PER have been shown not to exert antiepileptic activity [40]. Metabolites are excreted up to two-third (70%) via feces and to 30% renally [39]. Mild renal impairment may thus have only minor consequences for PER clearance. In a patient cohort with creatinine clearance of 50 -- 80 ml/min, PER clearance was, however, 27% lower compared to patients with normal creatinine clearance [38-40]. Data in severe renal impairment are not available so far. In contrast, patients already with mild and moderate hepatic impairment had an increase of mean halflife by 2.4/2.1, and AUC was 54/136% higher (Child--Pugh stadium A/B). According to impaired protein synthesis, total plasma concentrations were decreased by 30/21%, whereas free plasma concentrations increased by 26/18% [38-40]. The longer half-life in patients with hepatic impairment does necessitate a slower titration to assess PER tolerability [40]. 3.3

Interactions: effect of PER on other drugs Pharmacokinetic interactions of PER with other drugs can be based on competition of plasma protein binding and on effects on metabolism by CYP and uridine 3.4

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5’-diphospho-glucuronosyl transferase (UGT) enzymes. High protein binding of PER can be assumed to lead to marked changes in free concentrations of other drugs with strong protein binding. In vitro, PER at very high concentrations (30ymol/l) induces CYP3A4, CYP2B6, UGT1A4 and UGT 1A1 and inhibits CYP2C8, UGT1A9 and UGT2B7 [39,40]. In clinical studies, PER decreased oxcarbazepine (OXC) clearance by 26% and increased OXC plasma concentrations by 35%; the effects of the major metabolite 10--0 H-carbamazepine was, however, not analyzed. It remains to be determined how often increased OXC levels will lead to signs of intoxication in patients treated at dosages close to their individual tolerability limit. In an open-label drug interaction study with midazolam, a significant decrease in Cmax by 15% and a decrease of AUC by 13% were found [38]. Similarly, in clinical studies the clearance of carbamazepine, clobazam, lamotrigine and valproic acid was increased, but even at maximal clinically applied dosages of 12 mg/day this effect was < 10%. These interactions may thus be expected to play a clinically relevant role only in patients in whom there is a very delicate dependence of efficacy on minor plasma level alterations. In individual cases, however, decreases of plasma concentrations of phenytoin, phenobarbital and rufinamide by > 50%, however, have been reported [44]. PER (12 mg/day) was also shown to decrease Cmax and AUC values of levonorgestrel by 40%, whereas ethinyl estradiol was affected to a much lesser degree (Cmax: -18%, no relevant effect on AUC) [39]. The safety of hormonal contraception relying on effects of gestagens can thus be impaired, and other methods of contraception should be advised. 3.5

Interactions: effects of other drugs on PER

Enzyme-inducing AEDs increase clearance of PER and decrease PER plasma concentration, as shown by pooled analyses of clinical trials [38-40]. In increasing order, topiramate lowered mean PER AUC by 20%, both oxcarbazepine and phenytoin decreased PER AUC values by 50% and carbamazepine decreased PER AUC by 67%, resulting in a reduction of PER half-life by 56%. In contrast, other AEDs (clobazam, clonazepam, lamotrigine, levetiracetam, valproate and zonisamide) were not found to affect PER clearance. In regulatory trials in which PER dose was not adjusted to concomitant medication, efficacy was lower when enzyme inducers were present (50% responder rates in the 4, 8 and 12 mg groups; 23.0, 31.5 and 30.0% in combination with enzyme-inducing AEDs compared to 33.3, 46.5 and 50.0% without enzymeinducing AEDs [39]). Use of PER in combination with enzyme-inducing AEDs may thus necessitate higher dosages to achieve the same efficacy in seizure control than combinations with drugs which do not lead to hepatic induction. On the other hand, withdrawal of co-applied enzyme inducers may warrant reduction in the PER dose applied to avoid adverse effects related to increasing plasma levels. 1334

Elimination of PER Whereas PER had a short half-life in several mammalian species [23], in humans PER is only second to Brome in elimination time. Clearance of PER was 10.9 ml/min in healthy volunteers and 12 ml/min in epilepsy patients [38-40]. Phase III studies suggest minor gender differences, with slightly lower PER clearance in females (10.1 ml/min) [38,40,41] than in males (12.2 ml/min). Age also did affect the speed of elimination only to a minor degree with a clearance in adolescents of 13.1 ml/min compared to 10.4 -- 10.5 ml/min in a patient group aged 65 -- 76 years [40]. In clinical studies, the rate of elimination did not change over the time of exposure. Given these clearance rates in the human, PER has a mean elimination half-time of 105 h, which is far longer than in most other AEDs. There is considerable interindividual variability of t1/2 (53 -- 136 h in Phase I studies) [21], presumably depending on the degree of preexisting hepatic enzyme induction. The long plasma half-life of PER allows for once-daily dosing of the drug. Twice-daily dosing offers little advantage in reducing plasma concentration fluctuations, and a missed dose will induce only a minor reduction in the plasma profile [45]. This is of major advantage as Tmax-related side effects can be avoided with nightly administration and adherence to the intake is facilitated [46,47], and individual misses may have less severe impact on seizure control than with AED of short plasma half-time. For an overview of key pharmacokinetic data, see Table 1. 3.6

4.

Conclusion

PER introduces a new concept of synaptic modulation into the treatment of epilepsy. Its noncompetitive AMPA receptor blockade aims at rebalancing the delicate equilibrium between excitation and inhibition which is essential for normal functioning of the brain. Its efficacy in experimental acute seizure models and in chronic models of epilepsy has proven a good predictor for efficacy in human epilepsies with partial-onset seizures. Starting from add-on doses of 4 mg, significant reductions in seizure frequencies were found compared to placebo, and long-term extension studies confirmed the maintenance of its efficacy for periods of several years. During double-blind treatment, doses of 12 mg/day on average did not show stronger seizure reduction than 8 mg, whereas individually an improvement of seizure control may occur with uptitration beyond 8 mg/day. The unusual long plasma half-life of 105 h (Figure 1) not only offers advantages but also carries a risk for overtitration; waiting sufficiently long periods to assess tolerability and efficacy is essential to establish the optimal individual dose without risking avoidable adverse effects. Titration of PER needs to take into consideration that it will take 3 weeks to achieve steady state of plasma concentrations. An assessment of efficacy and tolerability thus needs to

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be done carefully over longer time periods to avoid overtreatment at dosages not needed to achieve the antiepileptic effect and to avoid unnecessary adverse effects [48]. Presently, prescribing schemes suggest to start with a dosage of 2 mg/day for 2 weeks before applying 4 mg/day; in adults, this initial step may not be necessary as treatment at a given dosage leads to quite gradual increases of plasma concentrations except for the time window of Tmax. Oral intake results in rapid and complete resorption; intake with meals slows the time until plasma levels are reached but does not affect the total dose available. Whereas the titration of PER needs patience on the side of patients and treating physicians, the long plasma half-life offers advantages as it allows once-daily dosing and reduces risks associated with forgetting the intake of individual doses, distinguishing PER from other AEDs in whom incompliance may not only be more frequent but also more severe in its consequences. With the presently available, unretarded formulations, a plasma serum peak occurs at 0.5 -- 2 h after oral intake. Options to reduce the impact of adverse effects related to Tmax include intake of PER with meals, reducing maximal serum concentrations (Cmax) and postponing Tmax without effecting the total bioavailability. Another option is to time PER intake to the time of sleep onset. This avoids the experience of the most common side effects of ataxia and somnolence and may even improve sleep in patients with disorders of falling asleep (personal observations). In patients with disorders of disturbed sleep, for example due to nycturia, however, ataxia may become manifest when patients get up during the night. Animal experiments had suggested a low safety margin regarding motor impairment [20]. In clinical practice, dizziness and somnolence rather than ataxia and gait disturbance have turned out to be the most common patients’ complaints. Although these adverse effects are common in AED treatment, specific concern has been raised due to case reports and one open-label extension study that reported severe neuropsychiatric side effects. These adverse effects appear to occur on a highly individual basis, possible more frequently in mentally retarded or previously psychiatric ill patients, and have occurred at a much higher rate when patients were treated at dosages of 10 -- 12 mg compared to an extension study using a less rigorous uptitration. This additionally supports the suggestion that dose escalation of PER should be performed with careful patient attention and monitoring, considering tolerability, not only focusing on motor performance and vigilance but also focusing on early indicators of behavioral or psychiatric adverse effects to recognize such potential adverse effects early on. PER is hepatically metabolized via the CYP450 system and glucuronyl transferases. It has only a minor enzyme-inducing effect, and major plasma concentration changes of co-applied AEDs have so far only been seen with oxcarbazepine. On the other hand, enzyme inducers do increase plasma clearance significantly, probably necessitating higher dosages to be

applied to obtain the same efficacy as with non-inducing drugs. So far, no differences in efficacy in combination with and without co-application of enzyme inducers have been noted. Overall, the simple dosing scheme, long plasma halflife and the particular mechanism of action render PER an interesting drug for polytherapy of difficult-to-treat epilepsies of focal origin. 5.

Expert opinion

PER offers a new concept to address the unmet need of improving seizure control in patients with partial-onset epilepsy. Reducing hyperexcitability by allosteric modulation of AMPA receptors introduces a strategy into clinical treatment which has been applied for a long period in experimental approaches widely used to suppress epileptic activity. This new pharmacodynamic approach distinguishes PER from other recently introduced AEDs modifying voltage-dependent cation channels, modulating synaptic transmitter release or focusing on an increased inhibition to counterbalance epileptic hyperexcitability. PER thus adds to the armamentarium of AED treatment and offers new options for combining distinct anticonvulsant treatment approaches. The efficacy of PER was proven in studies in patients with long-lasting uncontrolled epilepsy, resistant to previous treatments. There was a clear increase in efficacy up to a dose of 8 mg/day, whereas further increase seems to be advantageous only in patient subgroups, and possibly mostly to reduce severs seizure types. Whereas seizure reduction was a robust and significant result in several randomized, controlled regulatory trials and was maintained over longer periods of time in open extension studies, the number of patients achieving complete seizure control remained < 5% in these beststudied patient populations. Some reports on possibly less pharmacoresistant patient cohorts treated openly suggest that this percentage may be higher in clinical practice, but certainly PER like other new AEDs does not overcome the problem of incomplete seizure control in the most difficultto-treat patient group. There is a need to identify patient subpopulations which may particularly profit from PER treatment and to analyze which other AEDs show more than additive performance, allowing for new steps toward a rational polytherapy. Pharmacokinetics of PER provide particular advantages in dosing and thus for long-term compliance with intake. Whereas interactions with other drugs occur due to hepatic metabolism, the degree to which this poses problem in clinical practice is low. A slow release preparation might reduce peakdose-related side effects, but dosing prior to sleep onset in most cases does as well to avoid the perception of disturbing somnolence or dizziness. Although being far better tolerated than components acting on NMDA receptors, neuropsychiatric problems can arise and necessitate close monitoring during the introduction and dose escalation. PER may be a drug of late choice in patients with mental impairment and a history

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of psychiatric disturbances, however. In contrast, motor impairments suggested as a major tolerability problem from animal experiments play a lesser role and rarely limit clinical use of PER. Overall, the availability of PER in the add-on treatment of partial-onset seizures is an enrichment of the antiepileptic armamentarium available to the treating physician, offering relevant improvements beyond early treatment phases. There is a need to study cognitive tolerability, even if this appears rarely to be a patient complaint, and to identify subgroups which are best responders and patients particularly vulnerable to potential adverse effects. At present, a slow and careful introduction of PER is mandatory to evaluate efficacy and

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Affiliation Andreas Schulze-Bonhage MD, PhD Professor, University Hospital Freiburg, Epilepsy Center, Breisacher Str. 64, D-79106 Freiburg, Germany, Europe Tel: +49 761 270 53660; Fax: +49 761 270 50030; E-mail: [email protected]

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