New England Journal of Medicine publishes pharmacokinetic guided childhood absence epilepsy study by Capparelli et al.

Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. Given the complex variability in children’s development and metabolism, there were no studies ever conducted to determine which of these three drugs would be most effective as an initial empirical treatment.

That is, until now.

National researchers, including Edmund Capparelli, Pharm. D., Division of Pharmacology and Drug Discovery, Department of Pediatrics at UC San Diego, studied 453 children in a double-blind, randomized, controlled clinical trial. The treatments were randomly assigned to the physician, who would then prescribe it to the child newly diagnosed with childhood absence epilepsy. Drug doses were increase incrementally with systematic check-ups, until the child was free of seizures, the highest tolerable dose was reached, or a criterion that the treatment had failed. In addition to continuous seizures, attentional dysfunction was also an adverse effect.

Clinically, the goal was to do well-controlled dosage trials. This is the only study of its kind done in the pediatric population. The unique aspects of this study was that it incorporated comparative trials, a tight dose titration schedule that is checked along the way, with expected dosages using genomics and a child’s metabolism in different age groups.

Published in the New England Journal of Medicine, March 2010, the results of the study challenged an ongoing myth for the pharmaceutical consumer who perceives the newest drug on the market to be better than the old. According to the findings of this particular study, ethosuximide – a drug used for decades in treating children with absence epilepsy, proved to have the least adverse effects on children’s attention, and the newest drug – lamotrigine, was in fact the most ineffective. Valproic acid performed almost as well as ethosuximide.

Well, at least for initial empirical monotherapy in childhood absence epilepsy. According to Capparelli et al, ‘Even the best empirical therapy, however, fails in almost 50% of newly diagnosed cases.’ Given that there is an risk of recurrent seizures in these children as they get older, a more long-term follow up of the cohort is in progress.

It turns out, the more effective and tolerable drugs – ethosuxamide and valproic acid – work by different mechanisms, although they seem to achieve the same result. This is an important element to take into account as we advance towards personalized medicine – finding the right drug for the right patient.

“This study was 5-8 years all told – it was well thought-out, and well-executed. New drugs on the market today aren’t always used because they are more effective than the old ones. Many are sold primarily because of marketing,” Capparelli remarks. “We want to make sure that absolutely the best therapy is widely used, especially for children where the influence of varying dosages have serious effects on both their physical and cognitive development.”

Dr. Capparelli focuses his research on pharmacokinetic and pharmacodynamic modeling while specializing in pediatric clinical pharmacology. His clinical research expertise is widely recognized, as evidenced by his service to the following groups in this past year: World Health Organization (WHO) Pediatric Antiretroviral Dosing Working Group; Pediatric Antiretroviral Guidelines Working Group, US Department of Health and Human Services; NIH Workshop on Involvement of Children in TB Drug Development and FDA Clinical Pharmacology Subcommittee (CPSC) of the Advisory Committee on Pharmaceutical Sciences.

WRITTEN BY: Shivani Singh, Sr. Writer, Department of Pediatrics, UC San Diego s1singh@ucsd.edu

SCIENTIFIC CONTACT: Dr. Capparelli, Clinical Professor, Division of Pharmacology and Drug Discovery, Department of Pediatrics, ecapparelli@ucsd.edu