Abstract

Purpose: Modafinil is currently being evaluated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. A population pharmacokinetic model was developed describing the pharmacokinetics of modafinil film-coated tablets, including the time course of induction of CL/F, in patients aged 6 to 17 years.

Methods: Data included one Phase 1 (n=24) and four pooled Phase 3 (n=528) studies. Modafinil doses were titrated to a maximum 425 mg/day. Weight-based maximum doses were targeted for patients <30 kg (340 mg) and ≥30 kg (425 mg) in one Phase 3 study. Covariate models were evaluated using forward selection (=0.05), followed by backward elimination (=0.01).

Results: A two-compartment model with first-order absorption and elimination best fit the full-profile data from Phase 1. A one-compartment model with induction of CL/F adequately fit the pooled sparse data from Phase 3. Dependence of CL/F on weight was nonlinear, and was greater on Day 1 than after induction. CL/F was induced with a 12-day half-life. V/F was linearly related to weight [V/F (L)=29.2+0.696 (weight-38)]. Elimination half-life for youngest (lighter) patients (age 6) was 6 to 7 hours, and 9 to 10 hours for oldest (heavier) patients (age 17). Effects of BMI, age, dose, gender, and race were not statistically significant predictors of CL/F or V/F. Weight-based dosing consistently provided median exposures of approximately 150 μg·hr/mL at the primary visit of the Phase 3 studies.

Conclusions: The weight-based dosing strategy achieved target exposure of modafinil film-coated tablets in both weight groups. Induction of CL was complete by 7 weeks. After attainment of steady-state, no trend toward changes in pharmacokinetic properties was observed with up to 1 year of dosing.

American Association of Pharmaceutical Scientists (AAPS), Nashville, Tennessee, November 2005

By Joel S. Owen, Thaddeus H. Grasela, Philmore Robertson, Jr., Mona Darwish