Category: Clinical Pharmacology
Purpose: To compare brand versus generic (or generic versus generic) plasma pharmacokinetic (PK) profiles in epileptic patients who are generic brittle (GB), using various anti-epileptic drugs (AEDs).
Methods: The study employed a randomized, investigator-blinded, multiple-dose, fully-replicated four-way crossover design, where one test and one reference AED were dosed twice and compared in each patient with epilepsy. The study was not a bioequivalence study, but an exploratory PK study involving several AEDs. There were 16 patients who completed, involving seven different AED drug products with five different AED drug substances (i.e. topiramate tablet, lamotrigine ER tablet, levetiracetam IR tablet, levetiracetam ER tablet, carbamazepine ER tablet, carbamazepine ER capsule, and zonisamide capsule). For 13 patients, the reference product was brand, such that their switching was brand-to-generic. For three patients, reference and test products were different generics, such that their switching was generic-to-generic. Study drug in each patient was from the patient’s own AED regimen. In addition to patients being GB, the study drug was their most problematic AED in all subjects but one. At the end of each two-week treatment period, there was intensive PK blood sampling over the dosing interval (i.e. over 12 or 24 hr) for individual patient, 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: Pharmacokinetic profiles of test and reference products were similar in each patient, even though each patient was GB. In all subjects, mean ratios of test versus reference of AUCss and Cmax,ss were between 80-125%. For AUCss, mean(Standard Error of the Mean [SEM]) T/R ratio was 97.5%(1.7%) [range 84.2%-108.0%]. For Cmax,ss, mean(SEM) T/R ratio was 101.6%(2.3%) [range 84.7%-121.9%]. In all subjects, mean ratios of test versus reference of Cmin,ss were between 70-143%. For Cmin,ss, mean(SEM) T/R ratio was 96.3%(3.8%) [range 70.6%-140.9%].
Conclusion: Pharmacokinetic similarity was observed in all patients, who took seven different test and reference AED products. This pharmacokinetic similarity supports that physiologic systems that modulate drug disposition are not impacted by GB status (i.e., not impacted by patient opinion about generics).
Xiaohui Jiang– Silver Spring, Maryland
Wenlei Jiang– Senior Science Advisor, U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
Tian Liu– Baltimore, Maryland
Maureen Kane– University of Maryland School of Pharmacy, Baltimore, Maryland
Jeffrey Fink– Baltimore, Maryland
Tricia Ting– Washington, District of Columbia
James Polli– Professor and Ralph F. Shangraw/Noxell Endowed Chair in Industrial Pharmacy and Pharmaceutics, University of Maryland School of Pharmacy, Baltimore, Maryland