Bioequivalence of methylphenidate immediate-release tablets using a replicated study design to characterize intrasubject variability

Purpose. To determine the relative bioavailability of two marketed, immedia te-release methylphenidate tablets. The study used a replicated study desig n to characterize intrasubject variability, and determine bioequivalence us ing both average and individual bioequivalence criteria. Methods. A replicated crossover design was employed using 20 subjects. Each subject received a single 20 mg dose of the reference tablet on two occasi ons and two doses of the test tablet on two occasions. Blood samples were o btained for 10 hr after dosing, and plasma was assayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and more rapi dly absorbed in vivo than the reference product. The mean Cmax and AUC(0 - infinity) differed by 11% and 9%, respectively Using an average bioequivale nce criterion, the 90% confidence limits for the Ln-transformed Cmax and AU C(0 - infinity), comparing the two replicates of the test to the reference product, fell within the acceptable range of 80-125%. Using an individual b ioequivalence criterion the test product failed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent using an ave rage bioequivalence criterion. The intrasubject variability of the generic product was greater and the subject-by-formulation interaction variance was borderline high. For these reasons, the test tablets were not individually bioequivalent to the reference tablets.