title: Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate.
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.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC (K.S.P.); and Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (A.B.S.) patrickk@musc.edu.
authors.forename: Kennerly S
authors.initials: KS
authors.lastname: Patrick
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC (K.S.P.); and Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (A.B.S.).
authors.forename: Arthur B
authors.initials: AB
authors.lastname: Straughn
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000378:metabolism*; D064699:Dexmethylphenidate Hydrochloride / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000378:metabolism*; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D064699:Dexmethylphenidate Hydrochloride; D008774:Methylphenidate