Lack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteers

Abstract

To assess bioequivalence between Equasym Retard and Medikinet retard containing 20 mg methylphenidate (MPH) hydrochloride in a fed state. Equasym Retard 20 mg capsules (UCB, Monheim, Germany) and Medikinet retard 20 mg capsules (Medice, Iserlohn, Germany). This was an open, single-center, randomized, 2-period, 2-sequence, balanced cross-over study with a wash-out period of 1 week between administrations in 14 healthy male and female volunteers, aged 18 - 45 years. Blood samples were collected over 24 hours and methylphenidate plasma concentration-time data were used to calculate pharmacokinetic metrics for both formulations. The main metrics were AUC0-t and Cmax. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was 80 - 125% (AUC0-t, Cmax). All dosed subjects finished both treatment periods and were included in pharmacokinetic and safety analyses. The adverse events observed, mainly nervous system disorders (headache), were all mild or moderate in intensity and resolved without any action taken. The adverse event profile was consistent with the currently applicable SmPCs (Summaries of Product Characteristics) for Equasym Retard and Medikinet retard. Geometric means +/- SD for AUC0-t and Cmax were 35.5 +/- 10.1 ng x h/ml and 4.05 +/- 0.96 ng/ml (Equasym Retard) and 39.2 +/- 13.8 ng x h/ml and 5.26 +/- 2.11 ng/ml (Medikinet retard). The 90% geometric confidence interval for AUC0-t (extent of absorption) was within limits accepted for bioequivalence. Bioequivalence could not be demonstrated for the rate of bioavailability (Cmax); both the lower confidence limit and the point estimate were below 80% of the reference. The study has shown that both formulations lead to a similar pattern of absorption and elimination following single dose administration in the fed state, although the test formulation shows a somewhat slimmer profile, where the first peak is less pronounced. No bioequivalence could be shown within the first 4 hours. The second peak of the test was also lower than the one of the reference (both lower confidence limit and point estimate below 80%). The two formulations are not bioequivalent, especially if the rate and values within the first four hours after administration are taken into account.