René H. Levy

Progress report on new antiepileptic drugs: A summary of the Eigth Eilat Conference (EILAT VIII)

The Eigth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT VII, took place in Sitges, Barcelona from the 10th to 14th September, 2006. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference, whose main themes included a focus on status epilepticus (epidemiology, current and future treatments), evidence-based treatment guidelines and the potential of neurostimulation in refractory epilepsy. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on marketed AEDs introduced since 1989. This article summarizes the information presented on drugs in development, including brivaracetam, eslicarbazepine acetate (BIA-2-093), fluorofelbamate, ganaxolone, huperzine, lacosamide, retigabine, rufinamide, seletracetam, stiripentol, talampanel, valrocemide, JZP-4, NS1209, PID and RWJ-333369. Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and new extended release oxcarbazepine formulations, pregabalin, tiagabine, topiramate, vigabatrin, zonisamide and new extended release valproic acid formulations, and the antiepileptic vagal stimulator device are also presented.

Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII)

The Seventh Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT VII) took place in Villasimius, Sardinia, Italy from the 9th to 13th May 2004. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference,whose main themes included advances in pathophysiology of drug resistance, new AEDs in pediatric epilepsy syndromes, modes of AED action and spectrum of adverse effects and a re-appraisal of comparative responses to AED combinations. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on second-generation AEDs. This article summarizes the information presented on drugs in development, including atipamezole, BIA-2-093, fluorofelbamate, NPS 1776, pregabalin, retigabine, safinamide, SPM 927, stiripentol, talampanel,ucb 34714 and valrocemide (TV 1901). Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine,topiramate, vigabatrin, zonisamide, new oral and parenteral formulations of valproic acid and SPM 927 and the antiepileptic vagal stimulator device are also presented.

Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX).

The Ninth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT IX, took place in Sitges, Barcelona from the 15th to 19th of June 2008. Over 300 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included old and new AEDs in generalized epilepsies, novel formulations and routes of administration of AEDs, common targets and mechanisms of action of drugs for treating epilepsy and other central nervous system (CNS) disorders, and opportunities and perspectives in new AED discovery. Consistent with previous formats of this conference, a large part of the programme was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1989. Unlike previous EILAT manuscripts, the current (EILAT IX) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate (RWJ-333369), 2-deoxy-d-glucose, eslicarbazepine acetate (BIA-2-093), ganaxolone, huperzine, JZP-4, lacosamide, NAX-5055, propylisopropylacetamide (PID), retigabine, T-2000, tonabersat, valrocemide and YKP-3089. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in first and second tables and their proposed mechanisms of action are summarized in the third table.

Cytochrome P450 isozymes and antiepileptic drug interactions.

Summary: Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phe‐nytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition‐based interactions possible. PHT is eliminated principally by hydroxylation top‐HPPH, a reaction catalyzed primarily by CYP2C9 and secondarily by CYP2C19 (S‐mephenytoin hydroxylase). The principle of isoform specificity (drugs metabolized by the same iso‐form should exhibit interactions with the same inhibitors) was applied to the interactions of PHT with 17 inhibitors using two probes for CYP2C9, S‐warfarin and tolbutamide. Eleven of 17 interactions (sulfaphenazole, phenylbutazone, fluconazole, azapropazone, cotrimoxazole, propoxyphene, miconazole, amiodarone, disulfiram, metronidazole, and stiripentol) could be explained by inhibition of CYP2C9. The remaining interactions (felbamate, omeprazole, cimetidine, fluoxetine, imipramine, and diazepam) were attributed to inhibition of CYP2C19. For CBZ, studies utilizing chemical inhibitors, immunoinhibition, liver bank correlations, and expressed enzymes established that CYP3A4 is the main enzyme catalyzing formation of CBZ‐10, 11‐epoxide. This explains the pronounced interactions of CBZ with erythromycin, tro‐leandomycin, and other macrolide antibiotics (clarithromycin, josamycin, flurythromycin, and ponsinomycin). Work is in progress to explain the interactions of CBZ with other inhibitors. The literature contains no other information on isoforms involved in the metabolism of other major antiepileptic drugs.

Valproic acid dosage and plasma protein binding and clearance

Valproic acid clearance was determined in six normal subjects during a single‐dose (250‐mg) study and multiple‐dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12‐hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 ± 2.44 to 6.67 ± 1.25 ml/hr/kg between the single‐dose and the 500‐mg/day steps (p = 0.05). Clearance was unchanged between the 500‐ and 1,000‐mg/day steps despite a 44% increase in mean free fraction (0.0703 ± 0.0381 vs 0.1011 ± 0.0438, p < 0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 ± 71.0 to 72.0 ± 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500‐mg/day step, clearance increased from 6.76 ± 1.48 ml/hr/kg (1,000 mg/day) to 8.20 ± 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose‐related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.

Progress report on new antiepileptic drugs: A summary of the Tenth Eilat Conference (EILAT X)

The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3.

New Antiepileptic Drugs: Review on Drug Interactions

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.

Comparison of the Steady‐State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: The steady‐state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions.

Bidirectional interaction of valproate and lamotrigine in healthy subjects

To evaluate the steady‐state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady‐state therapeutic doses of valproate.

Valproic acid clearance: Unbound fraction and diurnal variation in young and elderly adults

Six young (22 to 25 years old) and six elderly (60 to 88 years old) healthy adults took valproic acid, 250 mg by mouth, at 8 AM and 8 PM for 5 days. On the fifth day, blood samples were drawn over each dosage interval. Both young and elderly subjects exhibited diurnal variability. Total and unbound clearances in the young and elderly subjects were about 10% and 15% higher during the evening. These changes led to lower total and unbound steady‐state and peak concentrations during the nighttime dosage interval. There were no differences in total steady‐state concentrations and kinetics computed from total concentrations between the young and elderly, but there were differences in unbound steady‐state concentrations and kinetics. Unbound clearances were 65% lower, which resulted in unbound steady‐state concentrations 67% higher in the elderly. The average unbound fractions in the elderly and young were 10.7% and 6.4%. To minimize the influence of diurnal variability, drug concentrations should be determined at the same time each day. Total valproic acid concentration data may be less useful in elderly patients; unbound concentrations may be more reliable in this population.