Childress Ann, Mehrotra Shailly, Gobburu Jogarao, McLean Angus, DeSousa Norberto J, Incledon Bev
1 The Center for Psychiatry and Behavioral Medicine , Las Vegas, Nevada.
2 Center for Translational Medicine, School of Pharmacy, University of Maryland , Baltimore, Maryland.
J Child Adolesc Psychopharmacol. 2018 Feb;28(1):10-18. doi: 10.1089/cap.2017.0044. Epub 2017 Oct 17.
Current extended-release (ER) formulations of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD) provide an extended duration of ADHD symptom control; however, the onset of efficacy can be protracted and variable, leaving the early morning untreated. The primary objective was to characterize the single-dose pharmacokinetics and tolerability of HLD200, an evening-dosed, delayed-release (DR) and ER formulation of methylphenidate (MPH), in healthy adults and in adolescents and children with ADHD.
The pharmacokinetics and tolerability of a single, oral evening dose of HLD200 (54 mg) were evaluated in two single-center open-label studies: the first in healthy adults (n = 12) and the second in adolescents (n = 18) and children (n = 11) with ADHD. Primary pharmacokinetic endpoints were the rate and extent of MPH absorption (C and area under the curve [AUC]) and time to peak concentration (T). These parameters were calculated using noncompartmental analysis.
HLD200 produced a pharmacokinetic profile characterized by an 8- to 10-hour delay in MPH release, followed by a period of extended controlled release, resulting in an ascending absorption profile that coincided with the early morning and afternoon. Mean values (coefficient of variation [CV]%) of weight-adjusted pharmacokinetic parameters were similar in adults and in adolescents and children with ADHD: C ([ng/mL]/[mg/kg]) was 9.1 (35.2), 8.8 (34.5), and 7.4 (30.1); AUC ([ng · h/mL]/[mg/kg]) was 126.5 (35.5), 129.4 (34.8), and 129.7 (27.3); and T (hours) was 15.6 (11.1), 17.1 (14.5), and 17.7 (14.1), respectively. Intersubject variability in the mean time to achieve ascending plasma MPH concentrations of 2, 3, 4, and 5 ng/mL was low (CV: 7.8%-17.7%).
Evening-dosed HLD200 produces the intended DR and ER pharmacokinetic profile that provides a consistent predictable delay in initial MPH release until the early morning, followed by extended release across the day. The body weight-adjusted pharmacokinetics of HLD200 were similar between adults and adolescents and children with ADHD.
目前用于治疗注意力缺陷多动障碍（ADHD）的精神兴奋剂缓释（ER）制剂可延长ADHD症状控制的持续时间；然而，疗效的起效可能延迟且多变，导致清晨时段无法得到治疗。主要目的是在健康成人以及患有ADHD的青少年和儿童中，对晚间服用的哌甲酯（MPH）缓释（DR）和ER制剂HLD200的单剂量药代动力学和耐受性进行特征描述。
在两项单中心开放标签研究中评估单次口服晚间剂量的HLD200（54毫克）的药代动力学和耐受性：第一项研究针对健康成人（n = 12），第二项研究针对患有ADHD的青少年（n = 18）和儿童（n = 11）。主要药代动力学终点指标为MPH吸收速率和程度（Cmax和曲线下面积[AUC]）以及达峰浓度时间（Tmax）。这些参数使用非房室分析方法进行计算。
HLD200呈现出一种药代动力学特征，即MPH释放延迟8至10小时，随后是一段延长的控释期，导致吸收曲线上升，与清晨和下午时段相吻合。体重校正的药代动力学参数平均值（变异系数[CV]%）在成人以及患有ADHD的青少年和儿童中相似：Cmax（[纳克/毫升]/[毫克/千克]）分别为9.1（35.2）、8.8（34.5）和7.4（30.1）；AUC（[纳克·小时/毫升]/[毫克/千克]）分别为126.5（35.5）、129.4（34.8）和129.7（27.3）；Tmax（小时）分别为15.6（11.1）、17.1（14.5）和17.7（14.1）。在达到血浆MPH浓度升为2、3、4和5纳克/毫升的平均时间方面，受试者间变异性较低（CV：7.8% - 17.7%）。
晚间服用的HLD200产生了预期的DR和ER药代动力学特征，在MPH初始释放方面提供了一致且可预测的延迟，直至清晨，随后全天持续释放。HLD200在成人以及患有ADHD的青少年和儿童中，经体重校正后的药代动力学相似。
