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

Akwete L Adjei, Inder Chaudhary, Scott H Kollins, Americo Padilla, Akwete L Adjei, Inder Chaudhary, Scott H Kollins, Americo Padilla

Abstract

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 (Cmax), area under the concentration-time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (Vd) 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 Cmax and area under the curve to the last measurable observation (AUC0-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 Cmax/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC0-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 Cmax ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized Cmax 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 Vd 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 Vd and relatively higher systemic MPH levels for children in the preschool group.

Trial registration: Clinicaltrials.gov Identifier: NCT02470234.

Conflict of interest statement

Akwete L. Adjei and Inder Chaudhary are employees of Rhodes Pharmaceuticals L.P. Scott H. Kollins receives research support and/or consulting fees from Aevi Genomic Medicine, Akili, Alcobra, Bose, Ironshore, Jazz, KemPharm, NLS, Purdue Canada, Rhodes Pharmaceuticals L.P., Shire, SK Life Science, and Sunovion. Americo Padilla has nothing to disclose.

Figures

Fig. 1
Fig. 1
Visual prediction check plots for methylphenidate from the final population pharmacokinetic model for a children aged 6–11 years and b preschool children aged 4 to < 6 years. Blue dots represent the observed data; red lines represent the quantiles for the observed data. The 5th (solid red line), 50th (dashed red line), and 95th (dotted red line) quantiles are shown for the observed data. The blue shaded regions represent the 90% prediction interval for the 5th and 95th quantiles. The red shaded region represents the 90% prediction interval for the 50th quantile. Data are shown regardless of the administered dose
Fig. 2
Fig. 2
Correlation of a CL/F with age and bCmax with age. Cmax maximum concentration, CL/F apparent clearance
Fig. 3
Fig. 3
Relationship between plasma methylphenidate concentrate and time in children aged 4 to 

Fig. 4

Dose-normalized mean methylphenidate concentration–time plot…

Fig. 4

Dose-normalized mean methylphenidate concentration–time plot for a observed data and b observed and…

Fig. 4
Dose-normalized mean methylphenidate concentration–time plot for a observed data and b observed and simulated data
Fig. 4
Fig. 4
Dose-normalized mean methylphenidate concentration–time plot for a observed data and b observed and simulated data

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