Single- and multiple-dose pharmacokinetics of an oral mixed amphetamine salts extended-release formulation in adults.

OBJECTIVES: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20, 40, and 60 mg. METHODS: Study A, an open-label single-period study, and Study B, a randomized, open-label, three-way crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20, 40, and 60 mg separated by 7-14-day washout periods. FINDINGS: Plasma dextroamphetamine (d-amphetamine) and levoamphetamine (l-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of d-amphetamine to l-amphetamine was observed for AUC0-inf and Cmax. Tmax was 4.2 and 4.3 hours for d-amphetamine to l-amphetamine, respectively. In Study B, for d- and l-amphetamine, statistically significant differences were observed for AUC0-t, AUC0-inf, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5-5.3 hours) with all given MAS XR doses. CONCLUSION: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of d-amphetamine to l-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

Simulation of the effect of patient nonadherence on plasma concentrations of carbamazepine from twice-daily extended-release capsules.

OBJECTIVE: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels. PATIENTS AND METHODS: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400-mg fasting dose of CBZ-ERC. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12 h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7 h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3, 6, or 9 h late, or when two doses are taken at one time. RESULTS: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4 microg/ml only to 4 microg/ml after 24 h without medication, and only to 2.5 microg/ml after 36 h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9 microg/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3 h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ. CONCLUSIONS: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.

A pharmacokinetic/pharmacodynamic study comparing a single morning dose of adderall to twice-daily dosing in children with ADHD.

OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic properties of once-daily versus twice-daily doses of Adderall. METHOD: Following a 1-week wash-out, 12 subjects with attention-deficit/hyperactivity disorder (ADHD) entered a double-blind crossover study comparing two conditions: QD (10 mg of Adderall at 7:30 a.m. and placebo at noon) or BID (10 mg of Adderall at 7:30 a.m. and at noon). At two sites, cohorts of six subjects each were assessed on two different days by a 12-hour laboratory school protocol. Plasma concentrations of d- and l-amphetamine, vital signs, teacher ratings of classroom behavior on the SKAMP, and 10-minute Math Test performance were measured repeatedly over 12 hours. An analysis of variance used center, subject-within-center, condition, and time-after-second-dose as independent variables. RESULTS: The pharmacokinetic profiles revealed similar morning concentrations of d- and l-amphetamine. However, concentrations were twice as high in the afternoon for BID as QD. The two conditions showed similar pharmacodynamic profiles in the morning, although improvement in math performance and behavior was maintained into the afternoon only in the BID condition (p <.05). CONCLUSIONS: This study suggests that twice-daily dosing of Adderall may be an effective strategy for afternoon control of attention and deportment for children with ADHD.