SEATTLE—Rational polypharmacy with antiepileptic drugs (AEDs) may be beneficial if monotherapy fails in patients with epilepsy, according to Tracy Glauser, MD. At the 62nd Annual Meeting of the American Epilepsy Society, Dr. Glauser discussed the criteria that physicians should consider in selecting AEDs for rational polypharmacy, examined the pharmacodynamic and pharmacokinetic factors involved with the drugs, and reviewed current animal and human research.
Although existing data are insufficient to make firm recommendations, the use of drugs with different mechanisms of action appears to be more effective than combining drugs with similar mechanisms, said Dr. Glauser. In addition, he suggested that the future of rational polypharmacy will involve a computational approach to help clinicians in the decision-making process.
Finding the Right Combination
“There’s a rich history of people trying to find combinations that work for a rational polypharmacy approach to difficult-to-treat epilepsy,” said Dr. Glauser, Professor of Pediatrics and Neurology at the University of Cincinnati and Director of the Comprehensive Epilepsy Program at the Cincinnati Children’s Hospital Medical Center. One of the first well-documented cases was the combination of bromides and digitalis, proposed as an effective rational polypharmacy combination by Hare in 1914. “This combination was focused on improving efficacy, but there were also combinations postulated to help reduce side effects,” noted Dr. Glauser. The combination of bromides and arsenic was thought to reduce the risk of rash for patients with epilepsy, and a common combination used in the early 1900s was bromides and belladonna. “Now, clearly, we didn’t use that in the Childhood Absence Epilepsy Study,” he commented. “But in the old days, that was the common use for treatment of pedi-mal epilepsy.” Other combinations have included zinc, iron, and opium.
In 2006, the International League Against Epilepsy published treatment guidelines identifying AED- and patient-specific variables that were useful in selecting medications for rational monotherapy. These same variables can be applied to rational polypharmacy, Dr. Glauser noted, “but the decision becomes exponentially more complicated because of the drug-drug interactions, not only between AEDs but [also] between AEDs and other drugs that the patient is taking.… We have to always look at efficacy and tolerability together, because without the other, you only get part of the picture.”
Pharmacodynamic Effects in Multidrug Regimens
Regarding pharmacodynamic factors of AEDs, “we want combinations that improve efficacy, or effectiveness, and we want combinations that don’t enhance toxicity or don’t make the neurotoxic effect of these drugs worse,” said Dr. Glauser. Examining the mechanism of action of AEDs is important in selecting medications that will enhance efficacy without worsening toxicity, he said. Major categories of AEDs in terms of mechanism of action include sodium channel blockers, calcium channel drugs, GABA enhancers, and glutamate blockers.
One pharmacodynamic approach is the isobolographic method, which evaluates whether there is a mutual interaction between two drugs that, when administered at clinically effective doses, has an additive, antagonistic, or synergistic effect. “We want drugs that have synergistic efficacy but infra-additive toxicity, meaning they don’t add up to more than you would expect in terms of side effects.”
Although animal data are lacking for all the potential combinations, existing models indicate that combining drugs with different mechanisms of action is more beneficial in efficacy and toxicity than a combination of drugs with similar mechanisms of action, such as two sodium channel drugs. “We need better animal models, we need better approaches to the clinical data, and we need new types of clinical trials to better answer these questions,” said Dr. Glauser.
Based on evidence from clinical trials, one AED combination may be worthy of future study, according to Dr. Glauser. In one large-scale, nonrandomized study of 345 patients, Brodie and colleagues observed a synergistic response in the interaction between lamotrigine and valproic acid. Patients had not achieved seizure control with valproic acid, carbamazepine, or phenytoin as monotherapy and were being transitioned to lamotrigine monotherapy. Converting patients from failed initial monotherapy to lamotrigine was associated with improved seizure control. More importantly, Dr. Glauser noted, when lamotrigine was added to valproic acid, “this particular subgroup did spectacularly well compared to the other two. ‘Spectacularly well’ is a code word for ‘statistically significantly better,’” he said.
In a study by Pisani et al, 20 patients with seizures resistant to other AEDs were given valproic acid, lamotrigine, or a combination of the two at three-month intervals. If no response was seen with the initial treatment of valproic acid, patients were administered lamotrigine; if this monotherapy was ineffective, they were given the combination. Three patients responded to valproic acid, while another four patients experienced a reduction in their seizures with lamotrigine. Of the remaining 13 patients given the combination of valproic acid and lamotrigine, four patients had a reduction in seizure frequency, and four patients became seizure-free.