Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate

The postulate that twice the milligram/kilogram dose of dl-methylphenidate (dl-MPH) would result in equal exposure to d-MPH compared with half that milligram/kilogram dose of the chiral switch product dexmethylphenidate (d-MPH) was tested. Using a randomized, crossover study design, 12 men and 12 women received either immediate-release (IR) dl-MPH (0.3 mg/kg) or IR d-MPH (0.15 mg/kg). Relative bioavailability comparisons included partial area under the plasma concentration-time curves (pAUC0-3 h) for d-MPH. The pAUC0-3 h is a new regulatory metric presently only required for bioequivalence testing of a specific dl-MPH modified-release product. The geometric mean ratios for both the Cmax and area under the plasma concentration-time curve (AUC0-∞) were within the 90% confidence interval (CI) regulatory range of 0.8-1.25, indicating that these two drugs were bioequivalent in terms of d-MPH. However, the pAUC0-3 h geometric mean ratio for d-MPH after IR dl-MPH versus IR d-MPH was 0.76 (P < 0.001; 90% CI, 0.67-0.87), showing significantly less early exposure to the d-isomer than IR d-MPH. The 1-hour d-MPH concentration after dl-MPH was 56% of that after the enantiopure drug. The maximum d-MPH plasma concentration (Cmax) for dl-MPH was also significantly lower for dl-MPH (P < 0.05; CI, 1.02-1.19), whereas the AUC0-∞ ratio of 0.89 was not significantly different (P = 0.21; CI, 0.98-1.13). The AUC0-3 h difference reported here points to the potential limitations of using bioequivalence for sound predictions of dose-response relationships. Knowledge of the greater early exposure to d-MPH after the pure d-isomer drug compared with the racemate may contribute to drug individualization/optimization in the treatment of attention deficit hyperactivity disorder.