Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system.
Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose-ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled-release formulation (OROS). Plasma concentrations of l-methylphenidate were 40-fold lower than those of d-methylphenidate, whereas plasma concentrations of d-alpha-phenyl-2-piperidine acetic acid (d-PPA) and l-PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d-methylphenidate were 42.2, 80.9, and 120 ng.h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l-methylphenidate were only approximately 1% of d-methylphenidate (0.43, 0.96, and 1.82 ng.h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d- and l-PPA were comparable. The dose-normalized d- and l-methylphenidate plasma concentration-time profiles for the three treatment groups were superimposable. Similarly, dose-normalized plasma concentrations of d- and l-PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d-methylphenidate AUCinf to d-PPA AUCinf and as l-methylphenidate AUCinf to l-PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS (methylphenidate HCl) exhibits dose-proportional and linear pharmacokinetics.
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ALZA Corporation, Department of Clinical Pharmacology, Mountain View, CA 94039, USA.
Wang
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B
Noveck
R J
RJ
Gupta
S K
SK
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008968:Molecular Conformation; D009995:Osmosis; D012737:Sex Factors
D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D008774:Methylphenidate