A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria
A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria
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DOI：
10.1046/j.1365-2125.1998.00655.x
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发表时间：
1998-02-01
影响因子：
3.4
通讯作者：
Kim, NV
中科院分区：
文献类型：
--
作者：
Batty, KT;Thu, LTA;Kim, NV
目的 获得青蒿琥酯 (ARTS) 及其活性代谢物二氢青蒿素 (DHA) 静脉注射后的全面药代动力学和药效学数据。方法 26 名患有恶性疟疾的越南患者被随机分配接受静脉注射或口服 ARTS 治疗。 ARTS（120 mg；第 1 组）或口服 ARTS（100 mg；第 2 组），并在 8 小时后以开放交叉设计给予替代制剂。 24 小时给予甲氟喹 (750 mg)。 ARTS 和 DHA 的血浆浓度通过 h.p.l.c 测定。化验。通过非房室法计算药代动力学参数。通过寄生虫密度测定的线性插值计算达到 50% 寄生虫清除的时间 (PCT50)。使用线性最小二乘法和多元线性回归分析来评估药代动力学-药效关系。推注时，ARTS的峰浓度为29.5μM(11mg·l(-1))，消除t(1/2)=2.7min，CL=2.33l·h(-1)·kg(-1)，V=0.14l·kg(-1)。 DHA的C-max为9.3μM(2.64mg·l(-1))，t(1/2)=40分钟，CL=0.75l·h(-1)kg(-1)，V=0.76l·kg(-1)。口服ARTS后，DHA的相对生物利用度为82%，C-max为2.6μM（0.74mg·l(-1)），t(1/2)=39分钟，MAT=67分钟。总体而言，PCT50 和退烧时间 (FCT) 分别为 6.5 小时和 24 小时。 PCT50或FCT与DHA的AUC、C-max或MRT之间没有相关性。 结论 尽管ARTS和DHA在无并发症的恶性疟疾患者中被快速清除，但仍实现了寄生虫和发烧的迅速清除。口服 ARTS 后 DHA 的相对生物利用度较高，临床结果与静脉注射后的结果相当。 ARTS，支持在初级保健环境中使用口服制剂。
Aims To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria.Methods Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT50) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic-pharmacodynamic relationships.Results Following i.v. bolus, ARTS had a peak concentration of 29.5 mu M (11 mg l(-1)), elimination t(1/2)=2.7 min, CL=2.33 l h(-1) kg(-1) and V=0.14 l kg(-1). The C-max for DHA was 9.3 mu M (2.64 mg l(-1)), t(1/2)=40 min, CL=0.75 l h(-1) kg(-1) and V=0.76 l kg(-1). Following oral ARTS, relative bioavailability of DHA was 82%, C-max was 2.6 mu M (0.74 mg l(-1)), t(1/2)=39 min, and MAT=67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, C-max or MRT for DHA.Conclusions Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.