Clinical pharmacokinetic characteristics of novel antiepileptic drugs

Abstract

The choice of an antiepileptic drug (AED) is usually based upon the epileptic seizure type. However, pharmacokinetic (PK) characteristics of AEDs may be valuable support in choosing the optimal therapeutic option for the individual patient. The novel (second and third generation) AEDs include: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. Although, these drugs belong to the same group, their individual PK characteristics differ. Gabapentin, unlike other new AEDs, is characterised by dose-dependent absorption, which is presumably caused by saturable L-amino acid transport system, and therefore its bioavailability ranges from 35-60%. Furthermore, gabapentin, pregabalin and vigabatrin are eliminated completely, while levetiracetam and topiramate are eliminated predominantly through the renal system. Therefore, PK variability of these individual drugs is less pronounced and more predictable in comparison to older AEDs. Their potential for drug interactions is minor, and consequently they have major clinical importance for patients with impaired hepatic function. On the other hand, felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide are eliminated via metabolic pathways, either cytochrome P (CYP) 450, or conjugation dependent transformation. Oxcarbazepine is a prodrug, and its active metabolite is licarbazepine. These drugs interact with other drugs, and disease conditions, which alter the activity of metabolic enzymes; thus these changes in PK commonly have clinical implications. Gabapentin, levetiracetam and tiagabine do not induce or inhibit hepatic metabolism enzymes. Felbamate demonstrated an inducing effect on CYP 3A4 isoenzyme, and inhibition effect on CYP 2C19 and on β-oxidation of valproic acid. Lamotrigine induces its own metabolism, and some reports imply a decrease of valproic acid levels during concomitant treatment with lamotrigine. Oxcarbazepine induces CYP 3A4, 3A5, and uridine diphosphate glucuronyl transfereases (UGT), and inhibits the metabolism of phenytoin via CYP 2C19 isoenzyme. Similar induction and inhibition characteristics are attributed to topiramate, while some studies indicate that zonisamide may have inhibition potential on phenytoin metabolism. In general, novel AEDs have linear PK, low plasma protein binding, and renal elimination, so their PK is more favorable in comparison with carbamazepine, phenobarbitone and valproic acid. This chapter gives a review of PK parameters of novel AEDs and its' variability based on age, comorbidities, concomitant therapy, and highlights the need of therapeutic drug monitoring.