Abstract
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.
Footnotes
- Received October 19, 2015.
- Accepted December 23, 2015.
This research was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant R01AA016707 (to K.S.P.)] and the South Carolina Clinical and Translational Research Institute, with an academic home at the Medical University of South Carolina, via use of the National Institutes of Health National Center for Advancing Translational Sciences [Grant UL1TR000062] and the National Institutes of Health National Center for Research Resources [Grant UL1RR029882]. Funding support for this work was solely received from the National Institutes of Health. No other funding could be construed as a conflict of interest. K.P. has been a consultant for Janssen, ALZA, Shire, Noven, and UCB within the last 3 years. K.P. has had a provisional patent for isopropylphenidate (ritalinic acid isopropyl ester) as a novel psychotropic agent, through the Medical University of South Carolina Foundation for Research Development, with a Notice of Abandonment in January 2014. A.S. is a member of the Board of Directors for Cingulate Therapeutics and has been a consultant for Watson.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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