Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict the potential for harmful or lacking effects involving AEDs.

During the period 1989-2009, 14 new antiepileptic drugs (AEDs) were licensed for clinical use and these can be subdivided into new second- and third-generation AEDs. The second-generation AEDs comprise felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. The third-generation AEDs comprise eslicarbazepine acetate and lacosamide. The interaction propensity of AEDs is very important because all new AEDs are licensed, at least in the first instance, as adjunctive therapy. The present review summarizes the interactions (pharmacokinetic and pharmacodynamic) that have been reported with the newer AEDs. The pharmacokinetic interactions include those relating to protein-binding displacement from albumin in blood, and metabolic inhibitory and induction interactions occurring in the liver. Overall, the newer AEDs are less interacting because their pharmacokinetics are more favorable and many are minimally or not bound to blood albumin (e.g., eslicarbazepine, felbamate, gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) and are primarily renally excreted or metabolized by noncytochrome P450 or uridine glucoronyl transferases (e.g., gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) as opposed to hepatic metabolism which is particularly amenable to interference. Gabapentin, lacosamide, levetiracetam, pregabalin and vigabatrin are essentially not associated with clinically significant pharmacokinetic interactions. Of the new AEDs, lamotrigine and topiramate are the most interacting. Furthermore, the metabolism of lamotrigine is susceptible to both enzyme inhibition and enzyme induction. While the metabolism of felbamate, tiagabine, topiramate and zonisamide can be induced by enzyme-inducing AEDs, they are less vulnerable to inhibition by valproate. Noteworthy is the fact that only five new AEDs (eslicarbazepine, felbamate, oxcarbazepine, rufinamide and topiramate) interact with oral contraceptives and compromise contraception control. The most clinically significant pharmacodynamic interaction is that relating to the synergism of valproate and lamotrigine for complex partial seizures. Compared with the first-generation AEDs, the new second- and third-generation AEDs are less interacting, and this is a desirable development because it allows ease of prescribing by the physician and less complicated therapeutic outcomes and complications for patients.

SUMMARYPregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly.Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED dose and serum concentration before pregnancy, and when that individual optimal concentration can be used as reference.

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