A Pharmacokinetic Study of Methylphenidate Hydrochloride Multilayer Extended-Release Capsules (Aptensio XR(®)) in Preschool-Aged Children with Attention-Deficit/Hyperactivity Disorder

OBJECTIVE: This was a single-dose, one-period, multicenter, pharmacokinetic (PK) study to evaluate the PK of methylphenidate (MPH) hydrochloride multilayer extended-release capsules (MPH-MLR) in preschool children aged 4 to < 6 years, previously diagnosed with attention-deficit/hyperactivity disorder (ADHD), and on a stable dose of MPH. METHODS: Preschool-aged children (N = 10) received a single oral dose of MPH-MLR (10, 15, or 20 mg) sprinkled over applesauce; a dose equivalent to their pre-enrollment daily dose of MPH. Blood samples for the measurement of MPH concentrations were obtained pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-dose. No structural model was assumed in the derivation of PK values for analysis. Maximum plasma concentration (C(max)), area under the concentration–time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (V(d)) data were compared with a historical group of older children aged 6–11 years (N = 11) and analyzed by bodyweight. Safety (adverse event monitoring, vital signs, electrocardiogram, clinical laboratory testing, physical examination) was assessed. RESULTS: Mean dose-normalized C(max) and area under the curve to the last measurable observation (AUC(0–t)) values were similar across dose groups, ranging from 0.67 ng/mL/mg (MPH 15 mg) to 0.81 ng/mL/mg (MPH 10 mg) for C(max)/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC(0–t)/dose. PK results were integrated into a previously described pharmacostatistical population PK model. Visual predictive check plots showed greater variability in the 6- to 11-year-old group than the 4- to < 6-year-old group, and CL increased with increasing body weight in a greater than dose-proportional manner. Mean CL, normalized for body weight, was constant for all dose groups, ranging from 4.88 L/h/kg to 5.80 L/h/kg. Median time to C(max) ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized C(max) concentrations indicated greater systemic exposures of MPH-MLR in preschool children aged 4 to < 6 years compared with children aged 6–11 years. Children aged 4 to < 6 years had a lower V(d) than children aged 6–11 years. There were no unexpected safety signals. CONCLUSION: The PK of MPH-MLR in preschool children demonstrated the biphasic absorption profile described earlier in older children, and the PK profile in children with ADHD aged 4 to < 6 years was similar to the profile in those aged 6–11 years, apart from a lower V(d) and relatively higher systemic MPH levels for children in the preschool group. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02470234. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40272-020-00409-z) contains supplementary material, which is available to authorized users.