A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: A case for carbamazepine

Background and objectives: Carbamazepine is among those drugs that have bee n considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administratio n has approved new generic products based on standard single-dose bioequiva lence studies, several state formularies, including the New Jersey Drug Uti lization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting th e use of some approved generic drugs in specific states. To further validat e the adequacy of single-dose studies for the determination of bioequivalen ce of narrow therapeutic index drugs, a multiple-dose study was conducted t hat more closely reflected therapeutic use. Methods: A single-center, multiple-dose, randomized, open-label, 2-way cros sover bioequivalence study was conducted in 32 fasting volunteers at steady state, Subjects received the test and reference products as a 200 mg carba mazepine tablet 3 times a day in a crossover fashion. Concentrations of car bamazepine and carbamazepine-10,11-epoxide in plasma were measured by a val idated specific HPLC method. Results: A total of 28 subjects completed the study, Pharmacokinetic parame ters and measures of fluctuation for both products at steady state were sim ilar, with 90% and 95% confidence intervals falling within 90% and 110%, Conclusion: The multiple-dose study provided reliable safety and bioequival ence data under rigorous statistical conditions and confirmed bioequivalenc e of test and reference products determined by a single-dose study.