Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers
Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers
复制标题
DOI：
10.1046/j.0306-5251.2001.01482.x
复制
发表时间：
2001-12-01
影响因子：
3.4
通讯作者：
Charles, BG
中科院分区：
文献类型：
--
作者：
Edstein, MD;Kocisko, DA;Charles, BG
目的描述健康志愿者接受他非诺喹后，他非诺喹的人口药代动力学的疟疾prevention.Methods人口由135名男性泰国士兵（平均年龄218.9岁，体重60.3公斤）。所有士兵都假定接受青蒿琥酯治疗3天，加强力霉素治疗7天，以消除任何先前存在的疟疾感染。104名战士（药物组）接受治疗方案后，接受他非诺喹400 mg负荷剂量每日3天，然后接受他非诺喹400 mg每月连续5个月。在安慰剂组中，31名士兵在研究期间感染了疟疾。他们再次接受青蒿琥酯治疗3天，强力霉素治疗7天，然后接受负荷剂量的他非诺喹400 mg/天治疗3天，然后每周接受400 mg他非诺喹预防治疗。随机抽取每月和每周一次预防性治疗的每位士兵的血样，用高效液相色谱法测定他非诺喹的血浆浓度。结果口服他非诺喹后的药代动力学符合一房室模型。年龄和体重影响分布容积（V/F），感染疟疾的受试者清除率（CL/F）较高，但认为这些因素均不足以影响剂量变化。一级吸收速率常数（K-a）、CL/F和V/F的群体估计值分别为0.694h（-1）、3.201h（-1）和18201。这些参数的受试者间变异性（变异系数，CV%）分别为61.2%、25.3%和14.8%。吸收和消除半衰期分别为1.0小时和16.4天。结论在野外条件下，泰国士兵口服他非诺喹的群体药代动力学已得到初步研究。这一信息，连同其已知的有效的抗疟疾活性，预示着他非诺喹作为一种有用的预防药物或用于间日疟的短期根治性治疗的应用。
Aims To describe the Population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis.Methods The Population consisted of 135 male Thai soldiers (mean age 218.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM.Results A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (K-a), CL/F and V/F were 0.694 h(-1), 3.20 1 h(-1) and 1820 1, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%.Conclusions The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.