Safety, Tolerability, and Pharmacokinetics of Intravenous Oseltamivir: Single- and Multiple-Dose Phase I Studies with Healthy Volunteers
Safety, Tolerability, and Pharmacokinetics of Intravenous Oseltamivir: Single- and Multiple-Dose Phase I Studies with Healthy Volunteers
复制标题
DOI：
10.1128/aac.00200-12
复制
发表时间：
2012-09-01
影响因子：
4.9
通讯作者：
Rayner, Craig R.
中科院分区：
文献类型：
--
作者：
Brennan, Barbara J.;Davies, Brian;Rayner, Craig R.
对静脉注射的需求还没有得到满足。神经氨酸酶抑制剂，特别是不能口服药物的严重流感患者。静脉注射二期I期药代动力学和安全性研究。奥司他韦在健康志愿者身上进行试验。第一个是开放标签、随机、四个周期、两个序列、单次给药的试验，分别为100 mg、200 mg和400 mg奥司他韦静脉注射。超过2小时，口服75毫克奥司他韦。第二项是一项双盲、安慰剂对照、平行分组、多次给药的研究，参与者被随机分为100 mg、200 mg奥司他韦或安慰剂(生理盐水)静脉注射。2小时以上，每12小时一次，连续5天。在静脉注射100毫克奥司他韦后，暴露于活性代谢物奥司他韦羧酸盐(OC)。超过2小时与口服75毫克相当。单次静脉注射。剂量高达400毫克的奥司他韦耐受性良好，没有新的安全信号。多剂量数据证实了100毫克和200毫克奥司他韦的良好耐受性，并显示100毫克静脉注射的OC暴露有效。2小时以上，每日2次，连续5天。这些结果支持了对静脉注射的进一步探索。奥司他韦作为无法服用口服药物的患者的流感治疗选择。
There is an unmet need for an intravenous (i.v.) neuraminidase inhibitor, particularly for patients with severe influenza who cannot take oral medication. Two phase I pharmacokinetic and safety studies of i.v. oseltamivir were carried out in healthy volunteers. The first was an open-label, randomized, four-period, two-sequence, single-dose trial of 100 mg, 200 mg, and 400 mg oseltamivir i.v. over 2 h and a 75-mg oral dose of oseltamivir. The second was a double-blind, placebo-controlled, parallel-group, multiple-dose study in which participants were randomized to 100 mg or 200 mg oseltamivir or placebo (normal saline) i.v. over 2 h every 12 h for 5 days. Exposure to the active metabolite oseltamivir carboxylate (OC) after dosing achieved with 100 mg oseltamivir administered i.v. over 2 h was comparable to that achieved with 75 mg administered orally. Single i.v. doses of oseltamivir up to 400 mg were well tolerated with no new safety signals. Multiple-dose data confirmed good tolerability of 100 mg and 200 mg oseltamivir and showed efficacious OC exposures with 100 mg i.v. over 2 h twice daily for 5 days. These results support further exploration of i.v. oseltamivir as an influenza treatment option for patients unable to take oral medication.