Invited Commentary Absorption differences between immediate - release dexmethylphenidate and dl - methylphenidate

The postulate that twice the mg/kg dose of dl-methylphenidate (dl-MPH) would result in equal exposure to d-MPH when compared to half that mg/kg 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 d-MPH concentration curves (pAUC0-3 hours) – a new regulatory metric presently only required for bioequivalence testing of a specific dl-MPH modifiedrelease product. The geometric mean ratios for both the Cmax and AUC0-inf were within the 90% confidence interval (CI) regulatory range of 0.8-1.25, indicating these two drugs were bioequivalent in terms of d-MPH. However, the pAUC0-3 hours geometric mean ratio for d-MPH following IR dl-MPH versus IR d-MPH was 0.76 (P < 0.001; CI 0.67-0.87), i.e., showing significantly less early exposure to the d-isomer than IR d-MPH. The 1 hour d-MPH concentration following dl-MPH was 56% of that following 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), while the AUC0-inf ratio of 0.89 was not significantly different (P = 0.21; CI 0.98-1.13). The AUC0-3 hours 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 following the pure d-isomer drug compared to the racemate may contribute to drug individualization/optimization in the treatment of attention-deficit/hyperactivity disorder (ADHD). This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward. Published on January 4, 2016 as DOI: 10.1124/dmd.115.067975 at A PE T Jornals on A uust 5, 2017 dm d.aspurnals.org D ow nladed from Nov 22, 2015 4 DMD# 67975