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Semi-Physiological based Population Pharmacokinetic Model for Methylphenidate Hydrochloride Multi-Layer Extended Release (Aptensio XR^®) Capsules in Children ages 4-12 and Adults

Andre J Jackson, Richard Brundage, Ene Ette, Inder Chaudhary

Aptensio XR^® is an Extended-Release (ER) Methylphenidate (MPH) capsule drug product, approved for use in patients 6 years and above. Clinical studies have been conducted in adults (N=24), children ages 6-12 (N=15), and pre-school children ages 4-5 (N=9) with approved doses in children aged 6 and above at 10, 15, 20, 30, 40, 50, and 60 mg. The purpose of this investigation is to determine if a semi-physiological model for ER MPH can adequately describe Aptensio XR^® (bead formulation) clinical data in children ages 4-12 and adults. Absorption of Aptensio XR^® in children has been characterized by two fast first-order releases and a delayed slow first-order release and in adults by a fast zero-order release and a delayed first-order release. Both are consistent with published MPH models for these demographic groups. Subject body weight, sex and age were important covariates. Model bioequivalence parameters in children and adults had 15% or less bias, except for pAUC_0-3 hours (partial area-under-the curve 0-3 hours) which was greater than 15% in children less than 6. The recommended starting dose of Aptensio XR for patients aged 6 years and above is 10 mg once daily in the morning with or without food. The model parameters in children were used for simulations to determine that the 10 mg dose was the best dose for the 4-5 year old children.