Epilepsy


Do New Antiepileptic Drugs with Novel Mechanisms of Action Suggest Reconsideration of Rational Polypharmacy?


Barry E Gidal, PharmD, RPh Professor of Pharmacy and Neurology, and Division Chair, School of Pharmacy, University of Wisconsin


Abstract


Although effective control of epilepsy can be achieved by a single antiepileptic drug (AED), the condition persists in a significant number of patients despite increasing dosages with monotherapy and polytherapy. Treatment with combinations of older AEDs has been known to cause undesirable drug–drug interactions and side effects. However, there has been renewed interest in polytherapy with the advent of newer AEDs with novel mechanisms of actions that are less likely to cause adverse effects in patients. Animal seizure models are useful for determining whether AEDs will be effective in generalised or partial seizures prior to clinical studies and isobolgraphic analysis may allow for a more systematic, rational approach to predicting whether a given combination of drugs will result in a greater or lesser pharmacologic effect. Since one treatment strategy does not suit all patients, studies should focus on the tolerability and safety of specific combinations of AEDs in order to provide guidance to physicians. In summary, pharmacokinetic interactions must be taken into account in studies in humans and animals with measurement of toxicity as well as efficacy.


Keywords Epilepsy, antiepilepsy drugs (AEDs), side effects, drug–drug interactions, polytherapy, seizure models, isobologram


Disclosure: Barry E Gidal, PharmD, RPh, has received research grants and speaker’s honoraria from GSK and UCB. Received: May 27, 2010 Accepted: June 25, 2010 Citation: US Neurology, 2010;6(1):70–6 Correspondence: Barry E Gidal, PharmD, RPh, School of Pharmacy and Department of Neurology, University of Wisconsin, 777 Highland Ave, Madison, WI 53705. E: begidal@pharmacy.wisc.edu


Support: The publication of this article was funded by UCB. The thoughts and opinions expressed are those of the author and not necessarily those of UCB.


Epilepsy is a common, complex, and chronic neurologic disorder affecting an estimated 0.5–1% of the global population or approximately 50 million people worldwide,1,2 the US.3


The ultimate goal of the treatment of epilepsy is to eliminate seizures without producing any side effects. Despite the plethora of antiepileptic drugs (AEDs) that have emerged over the past two decades, between 30 and 50% of patients continue to experience recurrent seizures.2,4


Established Antiepileptic Drugs and Their Limitations


Historically, treatment options for epilepsy have been limited.3 Epilepsy


is mostly managed using pharmacologic agents and major AEDs have included carbamazepine, phenobarbital, phenytoin, primidone, ethosuximide, and valproate. These older AEDs are generally effective, affordable, and familiar, but may cause hepatic dysfunction, drug interactions, and other significant side effects. This is reflected by the fact that between 1978 (when valproate was introduced) and 1993 (when felbamate received approval) no new anticonvulsants were approved by the US Food and Drug Administration (FDA).3 summarizes the potential targets for AED pharmacologic actions.


Figure 1 70


1.1–2.3 million of whom reside in


Many cases of newly diagnosed epilepsy can be successfully controlled with a single AED, but there are a significant number of patients in whom epilepsy persists despite receiving the highest dose of monotherapeutic AED. Polytherapy is the use of two or more medications to treat the same condition and is commonly used in the treatment of epilepsy when monotherapy fails. Since polytherapy is often unavoidable, it should be considered carefully before initiating a treatment regimen, as this carries a high risk for drug–drug interactions. Polytherapy may produce additive, antagonistic, or synergistic efficacy and toxicity.5


Unpredicted antagonistic


Many of the older AEDs have similar modes of action and therefore pharmacodynamic drug–drug interactions are common when used in combination.6


effects or heightened toxicity may result from the combination of AEDs with competitive hepatic enzymatic metabolism and protein binding interactions.5


Historically, polytherapy has been reserved for


medically intractable epilepsy due to the complexity of combining older AEDS;5


however, this practice should be reconsidered for earlier use in the treatment paradigm given the relatively cleaner profiles of the newer AEDs.


What Is Medically Intractable Epilepsy? Up to 30% of epileptic patients fail to go into remission despite appropriate treatment with AEDs.7,8


Although the characteristics of © TOUCH BRIEFINGS 2010


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