E-004 - EXTRAPOLATION OF EFFICACY OF A DEXTROAMPHETAMINE TRANSDERMAL SYSTEM (d-ATS) FROM PEDIATRIC (PED) TO ADULT POPULATIONS USING PHARMACOKINETIC (PK) MODELING.
Thursday, March 23, 2023
5:00 PM – 6:30 PM EDT
M. Castelli1, K. Suzuki2, K. Balakrishnan1, S. Meeves1, M. Komaroff1, J. Lennie3, J. Mondick3, S. Faraone4; 1Noven Pharmaceuticals, Inc., Jersey City, NJ, United States, 2Hisamitsu Pharmaceutical Co., Inc., Chiyoda-ku, Tokyo, Japan, 3Metrum Research Group, Tariffville, CT, United States, 4SUNY Upstate Medical University, Syracuse, NY, United States.
Background: Physiological similarities between ped and adult attention deficit/hyperactivity disorder (ADHD) patients (pts) and a tight link between PK and pharmacodynamic (PD) effects of amphetamine (AMP) in ADHD have been shown. In a pivotal study, d-ATS met efficacy endpoints for ADHD in children and adolescents, with d-ATS 15 mg deemed optimal for most pts. This work uses ped and adult PK data and model-based methods to extrapolate efficacy and safety findings from ped to adult pts.
Methods: A population PK (PopPK) model was developed using data from 7 PK studies to characterize AMP exposures after d-ATS administration. AMP exposures at 5, 10, 15, and 20 mg d-ATS were simulated for 1000 adults, adolescents, and children. AUC and Cmax were compared between age groups across dose levels.
Results: A one-compartment model with sequential zero- and first-order absorption adequately described AMP PKs. Body weight was the only clinically meaningful covariate. Simulated median (5th, 95th quantiles) AUC and Cmax values for adults administered 20 mg d-ATS were 1030 (701, 1520) ng·hr/mL and 46.2 (31.9, 66.0) ng/mL, respectively, comparable to values simulated for ped pts administered 15 mg d-ATS (AUC, 976 [624, 1560] ng·hr/mL; Cmax, 48.2 [29.4, 87.5] ng/mL). PK profiles for d-ATS in adults and children were similar, with one structural model fitting both groups’ data simultaneously.
Conclusion: A PopPK model demonstrated that AMP disposition was comparable across adult and ped ADHD pts after accounting for body weight. d-ATS 20 mg yielded exposures in adults similar to those from 15 mg in ped pts, a dose demonstrated as efficacious and deemed optimal in the pivotal ped study. Comparable AMP exposure in adults is likely to yield similar efficacy and safety outcomes, thus supporting the extrapolation of findings from ped pts to adults.
Wilens, T.E. & Spencer, T.J. Understanding attention-deficit/hyperactivity disorder from childhood to adulthood. Postgrad. Med. 122, 97-109 (2010).
Cutler, A.J. et al. Efficacy and safety of dextroamphetamine transdermal system for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: results from a pivotal phase 2 study. J. Child Adolesc. Psychopharmacol. 32, 89-97 (2022).
Center for Drug Evaluation and Research (CDER). Attention deficit hyperactivity disorder: developing stimulant drugs for treatment guidance for industry (Center for Drug Evaluation and Research (CDER), Rockville, MD, 2019).
