Abstracts

Rationale: To pharmacokinetically compare brand versus generic, or generic versus generic, plasma profiles in patients with epilepsy who are generic brittle (GB), using various antiepileptic drugs (AEDs). Methods: The study employed a randomized, investigator-blinded, fasted, multiple-dose, complete four-way replicate crossover design, where one test and one reference AED were compared in each epileptic patient. The study was not a bioequivalence study, but an exploratory pharmacokinetic study involving several AEDs. The study drug in each patient was from the patient’s own AED regimen. In addition to the patients being GB, the study drug was historically their most problematic AED in all subjects but one. At the end of each two-week treatment period, there was intensive pharmacokinetic blood sampling over the dosing interval (i.e., over 12 or 24 hr), along with trough measurements. Patients were permitted concomitant AEDs and other medications for comorbid disorders. AED was quantified using liquid chromatography-tandem mass spectrometry. Results: There were 16 patients who completed, involving five different AED drug substances and seven different drug products. For 13 patients, the reference product was brand, such that their switching was brand-to-generic. For three patients, the reference and test products were different generics, such that their switching was generic-to-generic. Test and reference pharmacokinetic profiles were similar in each patient, even though each patient was GB. In all subjects, the mean ratios of test versus reference of AUCss and Cmax,ss were between 80-125%. In all subjects, the mean ratios of test versus reference of Cmin,ss were between 70-143%. Conclusions: The pharmacokinetic similarity in all patients supports the premise that physiologic systems that modulate drug disposition are not impacted by GB status (i.e., not impacted by patient opinion about generics). Funding: Food and Drug Administration