用于治疗注意力缺陷多动障碍的新型哌甲酯每日一次制剂的研发：概念验证和产品验证研究。

Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies.

作者信息

Swanson James, Gupta Suneel, Lam Andrew, Shoulson Ira, Lerner Marc, Modi Nishit, Lindemulder Elizabeth, Wigal Sharon

机构信息

University of California, Irvine, Department of Pediatrics, Child Development Center, CA, USA.

出版信息

Arch Gen Psychiatry. 2003 Feb;60(2):204-11. doi: 10.1001/archpsyc.60.2.204.

DOI:10.1001/archpsyc.60.2.204

PMID:12578439

Abstract

BACKGROUND

The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance.

METHODS

Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study.

RESULTS

The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy.

CONCLUSIONS

These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.

摘要

背景

盐酸哌甲酯速释制剂的作用持续时间较短（3至4小时），人们认为每日给药3次可在12小时的日间时段内使疗效最大化。哌甲酯最初的缓释制剂与速释哌甲酯相比疗效降低，且未被广泛接受。据推测，快速耐受性是导致疗效降低的原因，因此提出了一种递增式给药模式来克服这种急性耐受性。

方法

在一所实验学校对患有注意力缺陷多动障碍的儿童进行评估，以确定各种哌甲酯治疗方案的起效时间和作用持续时间。在一项概念验证研究中，通过先给予一次大剂量负荷量，随后每30分钟给予递增小剂量的速释哌甲酯胶囊，持续8小时，建立了一种实验性递增给药模式。开展了两项关于一种新型口服一日一次制剂的产品验证研究，该制剂基于渗透泵技术（OROS，阿尔扎公司，加利福尼亚州山景城）递送哌甲酯（以下简称“OROS-哌甲酯”）：一项药代动力学研究和一项药效学研究。