13 Antiepileptic Drug Interactions

Philip N. Patsalos

Department of Clinical and Experimental Epilepsy, UCL-Institute of Neurology, London, UK
Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter, Buckinghamshire, UK

Introduction

Antiepileptic drug (AED) drug–drug interactions are commonly encountered in epilepsy treatment and represent a substantial challenge to physicians. There are various reasons for this: (1) although monotherapy AED is the therapeutic mainstay, AED combinations continue to be widely prescribed in patients who do not respond to monotherapy; (2) because of the chronic nature of epilepsy, the likelihood of AEDs being coadministered with other drugs for management of comorbidities is considerable; (3) many AEDs are potent inducers (e.g., carbamazepine, phenytoin, phenobarbital, primidone) or inhibitors (e.g., valproic acid, felbamate, stiripentol) of drug-metabolizing enzymes and are highly likely to modify pharmacokinetics of concurrently administered drugs; and (4) most AEDs have a narrow therapeutic index, with even modest changes in their plasma drug concentration resulting in seizure exacerbation or increased adverse effects.

SCIENCE REVISITED

Drug interactions can be divided into pharmacokinetic and pharmacodynamic types. Pharmacokinetic interactions are associated with a change in drug plasma concentration and are readily detectable and quantifiable with a well-characterized time course. Pharmacokinetic interactions can be due to a change in the absorption, distribution, metabolism, or excretion of the affected drug. These effects comprise most reported interactions, with most being the consequence of changes in hepatic metabolism. Pharmacodynamic interactions occur at the site of drug action in the brain and consequently are less well recognized and are usually concluded by default when a change in the clinical status consequent to a drug interaction is not associated with a change in a drug’s plasma concentration.

Anticipating and predicting metabolic interactions

Databases listing substrates, inhibitors, and inducers of different cytochrome P450 (CYP) isoenzymes are invaluable for predicting and avoiding potential interactions. For example, knowledge that carbamazepine is an inducer of CYP3A4 allows prediction that it will reduce the plasma concentration of CYP3A4 substrates such as ethosuximide, tiagabine, steroid oral contraceptives, and cyclosporin A. However, it must be appreciated that not all theoretically possible interactions highlighted in such databases will be clinically important. The most powerful predictor that an AED will not be associated with a pharmacokinetic interaction is that it does not undergo hepatic metabolism.

TIPS AND TRICKS

New steady-state blood concentrations are achieved by five half-lives of the drug that is inhibited, while enzyme induction completes by 3–4 weeks after introduction of the inducing drug. Only when these times have passed would the maximum therapeutic consequence of the interaction be observed clinically.

Prevention and management of adverse antiepileptic drug interactions

Antiepileptic drug interactions are prevented by avoiding polytherapy and selecting drugs with lower or absent potential to interact. A few simple rules, highlighted in Table 13.1, can assist in minimizing potentially adverse consequences of AED interactions.

Management comprises understanding the underlying mechanism of putative interactions to anticipate therapeutic outcome and close clinical monitoring. Also, with the aid of therapeutic drug monitoring, it is possible to ascertain the time course of the interaction and to implement appropriate dosing strategies, thereby circumventing undesirable consequences (seizure breakthrough or presentation of adverse effects).

Table 13.1. How to minimize potentially adverse consequences of AED interactions.

1	Only when there is a clear clinical indication should an additional AED be prescribed. Most patients with epilepsy (70%) are best managed with a carefully individualized dosage of a single AED.
2	Be aware of the most important pharmacokinetic interactions involving the drugs that you intend to prescribe and also their underlying mechanisms. Many interactions can be predicted based on knowledge of drug effects on specific liver isoenzymes. If appropriate, adjust dose to compensate for the predicted effects of the interaction.
3	Avoid combining AEDs with similar adverse effect profiles and whenever possible select combinations for which there is clinical evidence of a favorable pharmacodynamic interaction.
4	After adding/removing an AED, monitor the clinical response carefully and consider the possibility of an interaction if there is an unexpected change in response. Continue the observation for a period consistent with the pharmacokinetic and pharmacodynamic characteristics of the drugs involved. A dosage adjustment should be undertaken if necessary.
5	If a pharmacokinetic interaction is anticipated, monitor plasma concentration of the affected drug. Be aware that under certain circumstances (e.g., a displacement of drug from plasma proteins), routine total drug concentration measurements may be misleading and management may benefit from monitoring free drug concentration. Also, when a pharmacologically active metabolite is affected, it may be advantageous to monitor plasma concentration of the metabolite. In some cases, dosage adjustments may have to be implemented at the time the interacting drug is added or removed.
6	If a patient with epilepsy suffers from comorbidities that will require treatment with additional drugs, it is preferable to treat the epilepsy with an AED having a low interaction potential. Gabapentin, lacosamide, lamotrigine, oxcarbazepine, levetiracetam, pregabalin, topiramate, tiagabine, and vigabatrin have little or no ability to cause enzyme induction or inhibition. Among AEDs, the lowest interaction potential is associated with those that are renally eliminated (e.g., gabapentin, levetiracetam, pregabalin, and vigabatrin).
7	Likewise, when adding a drug to treat a comorbidity or an intercurrent condition, choose the drug from the needed therapeutic class that is least likely to cause problematic interactions.
8	Finally, ask patients to report any symptoms (e.g., seizure exacerbation or toxicity) that may suggest a drug interaction.

Figure 13.1 highlights the impact of AED interactions on clinical outcome, while a therapeutic algorithm illustrating management options in response to such interactions is summarized in Figure 13.2.

Pharmacokinetic interactions between antiepileptic drugs

A comprehensive summary of pharmacokinetic interactions between AEDs is given in Table 13.2. Those most relevant clinically are discussed briefly in the succeeding text.

Interactions mediated by enzyme induction

Carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of various CYP isoenzymes and also induce uridine glucuronyl transferases (UGTs) and epoxide hydrolases. As a result, these AEDs stimulate the metabolism of other concurrently administered AEDs, most notably clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine and its active monohydroxy metabolite, perampanel, rufinamide, stiripentol, tiagabine, topiramate, valproic acid, and zonisamide.

When AEDs are associated with pharmacologically active metabolites, the consequence of enzyme induction complicates the outcome of the interaction because, paradoxically, potentiation of the effects of the affected drug can occur. For example, with primidone, which is metabolized partly to phenobarbital, enhancement of metabolism in patients comedicated with phenytoin or carbamazepine may actually enhance the production of the latter metabolite and increase pharmacological effects. Although stimulation in valproic acid metabolism by enzyme-inducing AEDs typically results in decreased plasma levels and decreased effectiveness of valproic acid, this interaction may also lead to increased formation of hepatotoxic metabolites, which may explain why patients taking phenytoin, phenobarbital, or carbamazepine are more susceptible to valproate-induced liver toxicity. Other AEDs that are associated with pharmacologically active metabolites include carbamazepine, clobazam, oxcarbazepine, and eslicarbazepine acetate.

Interactions mediated by enzyme inhibition

Valproic acid is a notable inhibitor of drug metabolism resulting in three major interactions (i.e., with carbamazepine, phenobarbital, and lamotrigine) and two potentially moderate interactions (i.e., with felbamate and rufinamide). On average, the increase in plasma phenobarbital concentration after adding valproic acid is 30–50%, and a reduction in phenobarbital (or primidone) dosage by up to 80% may be required to avoid side effects, particularly sedation and cognitive impairment. The effect of valproic acid on lamotrigine metabolism involves inhibition of the UGT1A4 enzyme responsible for the glucuronide conjugation of lamotrigine, and inhibition of lamotrigine metabolism is already maximal at valproic acid doses within the usual target ranges (≥500 mg/day in adults).

Valproic acid can inhibit the enzyme epoxide hydrolase, which is responsible for metabolism of the pharmacologically active metabolite carbamazepine-10,11-epoxide. Thus, in patients co-prescribed carbamazepine and valproic acid, an increase in plasma carbamazepine-10,11-epoxide concentrations can occur without any marked changes in carbamazepine concentrations, resulting in toxicity.

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