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.