Population pharmacokinetic and exposure-response analyses of d-amphetamine after administration of lisdexamfetamine dimesylate in Japanese pediatric ADHD patients. Issue 6 (December 2020) - Tsuda, Yoshiyuki
Abstract: Lisdexamfetamine dimesylate, a prodrug of d -amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d -amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d -amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index. A total of 1365 points of plasma d -amphetamine concentrations from pediatric patients (6–17 years) with ADHD in clinical studies conducted in Japan and the US were employed for the population pharmacokinetic analysis. The plasma concentrations of d -amphetamine in pediatric patients with ADHD were well described by a one-compartment model with first-order absorption and lag time. The effects of body weight and ethnicity (Japanese or non-Japanese) on apparent total body clearance and the effect of body weight on apparent volume of distribution were incorporated into the final model. No clear exposure-dependent reduction was evident from the ADHD RS-IV total score, whereas the reductions were greater for the lisdexamfetamine dimesylate treatment groups compared with the placebo group regardless of exposure to d -amphetamine. Graphical abstract: Image 1