Assessing bioequivalence of generic antiepilepsy drugs

Objective: Patients with epilepsy are often concerned that switching between brand-name and generic formulations of antiepilepsy drugs (AEDs) may cause clinically significant changes in plasma drug concentrations. We assessed bioequivalence (BE) studies for approved generic AEDs to evaluate US Food and Drug Administration claims that: (1) generic AEDs are accurate copies of reference formulations; (2) delivery of reference formulations may be as variable as generic AEDs and so provide no increased benefit; and (3) switches between generic AED formulations are safe and effective. Methods: We determined differences in 90% confidence interval limits for total drug exposure (AUC _0-t) and peak concentration (Cmax) ratios of generic and reference formulations during fasting and fed BE studies. We simulated BE between generic formulations after adjusting for reference values. Results: AUC_0-t values of approved reference and generic formulations differed by <15% in 99% of BE studies; Cmax differed by <15% in 89% of studies. Food affected variability of Cmax but not AUC_0-t. Intersubject variability in Cmax and AUC_0-t was small and similar for reference and generic products. In simulated switches between 595 pairs of generic AED formulations, estimated AUC_0-t differed by >15% for 17% of pairs; estimated Cmax differed by >15% for 39%. AEDs with low bioavailability and solubility (eg, oxcarbazepine) had the greatest variability in BE. Interpretation: Most generic AED products provide total drug delivery (AUC) similar to reference products; differences in peak concentrations between formulations are more common. Switches between generic AED products may cause greater changes in plasma drug concentrations than generic substitutions of reference products.