Population pharmacokinetics of methylphenidate in children with attention-deficit hyperactivity disorder

Sources of individual variation in plasma methylphenidate (MP) concentratio ns during usual clinical use are not established. This was evaluated in a s eries of patients receiving clinical treatment with MP. A single plasma MP concentration was determined in each of 273 children and adolescents ages 5 to 18 years (mean: 11.1 years) who were clinically good responders to MP f or the treatment of attention-deficit hyperactivity disorder. MP was given on a twice-daily schedule (mean dose: 25 mg/day) in 40% of patients and thr ee times daily (mean dose: 39.3 mg/day) in 60%. A nonlinear regression mode l was applied to estimate overall population values of MP clearance and eli mination half-life (t(1/2)) assuming a one-component model with first-order absorption and elimination, and further assuming that clearance is linearl y related to body weight. The model incorporated each patient's dosage size and schedule, body weight, and time of the plasma sample. Iterated solutio ns of best fit were: t(1/2), 4.5 hours (95% confidence interval [CI]: 3.1-8 .1 hours), and apparent clearance, 90.7 ml/min/kg (95% CI: 74.6-106.7 ml/mi n/kg). The model explained 43% of the overall variance in MP concentrations (r(2) = 0.43, P < .001). In a small subsample [N = 16), a second plasma sa mple was drawn at the same time of day and at the same dose; the correlatio n between the two concentration values was 0.83. The relatively noninvasive approach used in this study allows the assessment of pharmacokinetic prope rties of medications under conditions of appropriate clinical use in specia l populations such as children, adolescents, and the elderly. Journal of Cl inical Pharmacology, 1999;39:775-785 (C) 1999 the American College of Clini cal pharmacology.