Ermer James C, Shojaei Amir, Pennick Michael, Anderson Colleen S, Silverberg Arthur, Youcha Sharon H
Shire Development Inc., Wayne, PA 19087, USA.
Curr Med Res Opin. 2007 May;23(5):1067-75. doi: 10.1185/030079907x182095.
To compare the single-dose pharmacokinetics of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation, with MAS extended release (MAS XR) (Adderall XR) + MAS immediate release (MAS IR) administered 8 h later.
This was a phase I, randomized, open-label, single-dose, single-center, two-period, crossover study in healthy adult volunteers designed to evaluate the bioavailability of triple-bead MAS over the course of a full day. Subjects were randomized to triple-bead MAS 37.5 mg or MAS XR 25 mg + MAS IR 12.5 mg administered 8 h later (MAS XR + MAS IR). The reference treatment was designed to mimic the clinical practice of providing extended coverage by supplementing a morning dose of MAS XR with a dose of MAS IR 8 h later in order to increase the duration of action. Plasma was assayed for d-amphetamine and l-amphetamine. Treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms (ECGs), and laboratory data were also collected for safety evaluation.
Exposure to d- and l-amphetamine was equivalent between triple-bead MAS and MAS XR + MAS IR based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)). For Cmax, least-squares mean ratios comparing triple-bead MAS with MAS XR + MAS IR were 101.0% and 90.9% for d-amphetamine and l-amphetamine, respectively, and for AUC(0-infinity) were 104.4% and 95.3% for d-amphetamine and l-amphetamine, respectively. Median time to maximum observed plasma concentration (Tmax) values for d-amphetamine and l-amphetamine were 8.0 h for triple-bead MAS and 10.0 h for MAS XR + MAS IR. There were no clinically meaningful differences between the study formulations for TEAEs or laboratory values. One subject experienced an ECG abnormality (asymptomatic premature ventricular contractions) leading to early termination from the study.
In healthy adults, the exposure observed with triple-bead MAS 37.5 mg was bioequivalent to MAS XR 25 mg supplemented by MAS IR 12.5 mg administered 8 h later. These data demonstrate that a single morning dose of triple-bead MAS provides equivalent plasma concentrations to those observed with a dose-augmentation strategy of MAS XR in the morning followed by MAS IR in the afternoon, while minimizing peak-to-trough fluctuations. Triple-bead MAS was also generally well-tolerated in this study.
比较三珠混合苯丙胺盐（MAS）（一种口服、每日一次的增强型缓释苯丙胺制剂）与8小时后给予的MAS缓释剂（MAS XR）（安非他明缓释片）+MAS速释剂（MAS IR）的单剂量药代动力学。
这是一项在健康成年志愿者中进行的I期、随机、开放标签、单剂量、单中心、两阶段交叉研究，旨在评估全天三珠MAS的生物利用度。受试者被随机分为接受37.5mg三珠MAS或8小时后给予25mg MAS XR + 12.5mg MAS IR（MAS XR + MAS IR）。参考治疗旨在模拟临床实践，即通过在早晨给予MAS XR剂量后8小时补充一剂MAS IR来提供延长的覆盖范围，以增加作用持续时间。检测血浆中的右旋苯丙胺和左旋苯丙胺。还收集治疗中出现的不良事件（TEAE）、生命体征、心电图（ECG）和实验室数据进行安全性评估。
基于最大血浆浓度（Cmax）以及从时间0至无穷大的血浆浓度 - 时间曲线下面积（AUC(0 - infinity)），三珠MAS与MAS XR + MAS IR之间的右旋和左旋苯丙胺暴露量相当。对于Cmax，比较三珠MAS与MAS XR + MAS IR的最小二乘均值比，右旋苯丙胺和左旋苯丙胺分别为101.0%和90.9%，对于AUC(0 - infinity)，右旋苯丙胺和左旋苯丙胺分别为104.4%和95.3%。三珠MAS的右旋苯丙胺和左旋苯丙胺达到最大观察血浆浓度（Tmax）值的中位时间为8.0小时，MAS XR + MAS IR为10.0小时。研究制剂在TEAE或实验室值方面没有临床意义上的差异。一名受试者经历了心电图异常（无症状室性早搏），导致提前退出研究。
在健康成年人中，观察到的37.5mg三珠MAS的暴露量与8小时后给予25mg MAS XR补充12.5mg MAS IR的情况生物等效。这些数据表明，早晨单次服用三珠MAS可提供与早晨采用MAS XR剂量增加策略随后下午服用MAS IR所观察到的等效血浆浓度，同时将峰谷波动降至最低。在本研究中，三珠MAS总体上耐受性良好。
