Rhodes Pharmaceuticals L.P., 498 Washington St., Coventry, RI, 02816, USA.
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
Paediatr Drugs. 2020 Oct;22(5):561-570. doi: 10.1007/s40272-020-00409-z.
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.
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), area under the concentration-time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (V) 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.
Mean dose-normalized C and area under the curve to the last measurable observation (AUC) 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/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC/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 ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized C 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 than children aged 6-11 years. There were no unexpected safety signals.
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 and relatively higher systemic MPH levels for children in the preschool group.
Clinicaltrials.gov Identifier: NCT02470234.
这是一项单剂量、单周期、多中心的药代动力学（PK）研究，旨在评估 4 岁至<6 岁以前被诊断患有注意缺陷多动障碍（ADHD）且稳定接受哌醋甲酯（MPH）治疗的学龄前儿童单次口服盐酸哌甲酯多层缓释胶囊（MPH-MLR）的 PK。
学龄前儿童（N=10）接受了 10、15 或 20mg 撒在苹果酱上的 MPH-MLR 单口服剂量；该剂量相当于他们入组前每天的 MPH 剂量。在给药前和给药后 0.5、1、2、3、4、6、8、10、12 和 24 小时采集血样以测量 MPH 浓度。在分析 PK 值时，没有假设结构模型。比较了最大血浆浓度（C）、浓度-时间曲线下面积（AUC）、消除半衰期、清除率（CL）和分布容积（V）数据，并根据体重进行了分析。评估了安全性（不良事件监测、生命体征、心电图、临床实验室检查、体格检查）。
在剂量组之间，剂量归一化的 C 和 AUC 到最后可测量的观察值（AUC）值相似，范围从 0.67ng/mL/mg（MPH 15mg）到 0.81ng/mL/mg（MPH 10mg）为 C/剂量，从 7.80h×ng/mL/mg（MPH 20mg）到 8.92h×ng/mL/mg（MPH 10mg）为 AUC/剂量。PK 结果被整合到先前描述的药代动力学群体 PK 模型中。视觉预测检查图显示，6-11 岁组的变异性大于 4-<6 岁组，CL 以大于剂量比例的方式随体重增加而增加。以体重标准化的平均 CL 在所有剂量组中保持不变，范围为 4.88L/h/kg 至 5.80L/h/kg。C 的中位数时间范围为给药后 2.00 至 3.00 小时，总体而言，与 6-11 岁儿童相比，4-<6 岁儿童 MPH-MLR 的剂量归一化 C 浓度表明系统暴露更大。4-<6 岁儿童的 V 低于 6-11 岁儿童。没有出现意外的安全信号。
学龄前儿童 MPH-MLR 的 PK 表现出与以前在较大儿童中描述的双相吸收特征一致，4-<6 岁患有 ADHD 的儿童的 PK 特征与 6-11 岁儿童相似，除了 V 较低和相对较高的系统 MPH 水平外为学龄前儿童组。
Clinicaltrials.gov 标识符：NCT02470234。
