MAP Pharmaceuticals, Inc, Mountain View, California 94043, USA.
Clin Ther. 2012 Sep;34(9):1920-8. doi: 10.1016/j.clinthera.2012.08.001. Epub 2012 Aug 21.
MAP0004 is an orally inhaled investigational drug containing dihydroergotamine (DHE). Although DHE has been used for 60 years with no reported cardiac arrhythmias, a thorough QT study had not previously been performed with DHE.
The objective of this study was to assess the effects of MAP0004 on the QT interval as required for regulatory approval of a new product.
This randomized, double-blind, placebo-controlled, 3-period crossover study enrolled healthy volunteers. Subjects were assigned to receive, in randomized sequence, MAP0004 at a supratherapeutic dose (3-fold the clinically effective dose) (3.0 mg), moxifloxacin 400 mg, or inactive vehicle, each administered with 1 placebo capsule. Triplicate ECGs were performed continuously at baseline (day 0), before dosing, and over 24 hours after dosing in each treatment period. The effect on the QT interval was assessed using the Fridericia (QTcF) and individualized (QTcI) correction formulas.
Fifty-four healthy adults (20 men, 34 women; mean age, 28 years) completed the trial and had measurable plasma levels of DHE after MAP0004 administration. The largest observed mean difference in QTcI between MAP0004 and placebo was 0.08 msec, and the largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after dosing. In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec relative to placebo, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity was sufficient to detect MAP0004-related effects. Nausea (27.8%) was common following MAP0004 administration but apparently did not influence the QTc interval.
A supratherapeutic dose of MAP0004 was not associated with prolonged QTc intervals. At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to affect the QT interval. MAP0004 and its primary metabolite showed no evidence for prolongation of the QTc interval in healthy subjects according to the criteria required from regulatory agencies. ClinicalTrials.gov identifier: NCT01191723.
MAP0004 是一种含有二氢麦角胺（DHE）的口服吸入式研究药物。尽管 DHE 已经使用了 60 年，没有报告心律失常，但之前没有进行过 DHE 的全面 QT 研究。
本研究的目的是评估 MAP0004 对 QT 间期的影响，以获得新产品的监管批准。
这是一项随机、双盲、安慰剂对照、三周期交叉研究，纳入了健康志愿者。受试者按随机顺序分配，分别接受超治疗剂量（临床有效剂量的 3 倍）（3.0mg）的 MAP0004、莫西沙星 400mg 或安慰剂载体，每种药物均与 1 个安慰剂胶囊一起给药。在每个治疗期的基线（第 0 天）、给药前和给药后 24 小时连续进行 3 次心电图检查。使用 Fridericia（QTcF）和个体化（QTcI）校正公式评估 QT 间期的影响。
54 名健康成年人（20 名男性，34 名女性；平均年龄 28 岁）完成了试验，并在 MAP0004 给药后测量到可测量的 DHE 血浆水平。MAP0004 与安慰剂相比，观察到的最大 QTcI 平均差异为 0.08msec，最大单侧 95%置信上限为 2.24msec，均在给药后 30 分钟。相比之下，莫西沙星使 QTcI 相对于安慰剂增加了 9.57 至 11.28msec，单侧 95%下限为 7.23 至 8.96msec，证实该测定法具有足够的灵敏度来检测 MAP0004 相关的影响。给药后 MAP0004 常见恶心（27.8%），但显然不影响 QTc 间隔。
超治疗剂量的 MAP0004 不会导致 QTc 间隔延长。在拟议的临床剂量（1.0mg）下，MAP0004 不太可能影响 QT 间期。MAP0004 及其主要代谢物在健康受试者中没有证据表明根据监管机构的要求延长 QTc 间期。临床试验.gov 标识符：NCT01191723。
