Modifications of antiepileptic drugs for improved tolerability and efficacy

Abstract

Introduction: A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties.

Material and method: AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches.

Results and discussion: Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABA(A) receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone).

Conclusion: Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders.

Keywords: antiepileptic drugs; chemical modification; efficacy; monitoring; pharmacodynamics; pharmacokinetics; tolerability.

Figure 1

Main proposed mechanisms of action of newer antiepileptic drugs (AEDs) in the inhibitory GABAergic and the excitatory glutamatergic synapse. The black spots are reuptake proteins for GABA and glutamate (two distinct, selective proteins). The grey receptor sites are metabotropic receptors, GABA_B for GABA and mGluR, for glutamate. Abbreviations: SV2A: synaptic vesicle protein 2A, the specific binding site for levetiracetam; VGCC and VGSC are voltage-gated calcium- and sodium channels, respectively. (Modified from Johannessen Landmark, 2007).

Figure 2

Pharmacokinetic paramaters. A drug is absorbed to the systemic circulation, where the drug may be bound to plasma proteins or distributed throughout body tissues (fat or fluid). It is only the free fraction of the drug in plasma that can exert an effect. From the systemic circulation the drug is transported to its site of action to exert its pharmacodynamic effect. The drug is undergoing elimination via biotransformation through metabolic pathways and elimination (often through liver, kidneys and faeces). The block arrows point to modifications in efficacy by pharmacodynamic (mechanism of action) factors, and tolerability by modifications of pharmacokinetic parameters.

Figure 3

Valproic acid, its toxic metabolite and several of the valproic acid analogues.

Figure 4

Metabolism of carbamazepine and its derivative oxcarbazepine and eslicarbazepine.

Figure 5

Felbamate and its derivatives, fluorofelbamate and carisbamate (RWJ 33369). The cleavage of felbamate to the toxic metabolite ATPAL is illustrated by the dashed line.

Figure 6

Lamotrigine and its derivative JZP-4.

Figure 7

The main inhibitory and excitatory amino acid neurotransmitters in the brain, GABA and glutamate, respectively.

Figure 8

Levetiracetam and its derivatives brivaracetam and seletracetam.

Figure 9

Gabapentin and its derivatives pregabalin and XP13512.

Figure 10

Topiramate and compounds with similar mechanism of action at the AMPA receptor.

Figure 11

Agonists at the GABA_A receptor, benzodiazepines and progesterone derivatives.