Methylphenidate bioavailability from two extended-release formulations

The objective of these studies was to compare the rate and extent of absorption of d,l-threo-methylphenidate (MPH) from two extended-release products--a capsule formulation containing coated beads and an OROS tablet formulation--in healthy male and female subjects under fasted conditions.

Metadate CD (methylphenidate HCl, USP) Extended-Release Capsules and Concerta (methylphenidate hydrochloride) Extended-Release Tablets.

Two studies were conducted: (1) A single dose, randomized, two-way crossover study in 36 adults comparing a 20 mg capsule and an 18 mg tablet, and (2) a single dose, randomized, four-way crossover study in 24 adults comparing 2 x 20 mg capsules, one 36 mg tablet, 3 x 20 mg capsules and one 54 mg tablet. Blood samples were collected over 24 hours and MPH plasma concentrations were used to calculate pharmacokinetic parameters for each treatment. Equivalence of pharmacokinetic parameters for comparable doses of the formulations was concluded if the 90% confidence intervals (CI) for the ratio between test and reference means were within the 80-125% equivalence criterion.

Both formulations exhibited biphasic plasma concentration-time profiles and were equivalent in terms of total exposure (AUC(0-last) and AUC(0-infinity)). However, early exposure (AUC(0-4) and AUC(0-6), the first maximum measured plasma concentration (C(max-1), and early plasma MPH concentrations (1.5, 3 and 4 hours) were greater with the capsule formulation, while later plasma MPH concentrations (8, 10 and 12 hours) were greater with the tablet formulation (the CIs were outside the 80-125% required for equivalence and p < 0.001 for all). Similar results were obtained whether or not the data were normalized for the difference in total dose.

The two formulations are not bioequivalent. The capsule fonnulation produces greater exposure to MPH and higher MPH concentrations during the first 6 hours following dosing. MPH is frequently used in school children, and this period would correspond to a major part of the school day.