Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria.
Assessment of the pharmacokinetics and dynamics of two combination regimens of fosmidomycin-clindamycin in patients with acute uncomplicated falciparum malaria.
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DOI：
10.1186/1475-2875-7-225
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发表时间：
2008-10-31
期刊：
影响因子：
3
通讯作者：
Na-Bangchang, Kesara
中科院分区：
文献类型：
--
作者：
Ruangweerayut, Ronnatrai;Looareesuwan, Sornchai;Hutchinson, David;Chauemung, Anurak;Banmairuroi, Vick;Na-Bangchang, Kesara
本研究调查了急性无并发症恶性疟疾患者在两种剂量方案下联合使用磷司米霉素和克林霉素的药代动力学。药代动力学研究共招募了70例符合入组标准的急性无并发症恶性疟原虫疟疾患者。患者接受两种不同剂量方案的磷咪霉素联合克林霉素治疗，具体如下：I组：磷咪霉素（900 mg）和克林霉素（300 mg），每6小时一次，持续3天（n = 25）; II组：磷咪霉素（1，800 mg）和克林霉素（600 mg），每12小时一次，持续3天（n = 54）。两种方案均耐受良好，无严重不良事件。组I和组II的28天治愈率分别为91.3%和89.7%。首次给药后约24小时，磷司米霉素和克林霉素达到稳态血浆浓度。磷司米霉素和克林霉素的药代动力学分析的模型独立和模型依赖性的方法，一般在广泛的协议。磷司米霉素和克林霉素作为两种不同的联合用药方案时，其药代动力学特征有显著差异。一般而言，接受高剂量方案的患者（第II组）的大多数剂量依赖性药代动力学参数（模型无关Cmax：3.74 vs 2.41 μg/ml; Cmax-ss：2.80 vs 2.08 μg/ml; Cmax-min-ss：2.03 vs 0.71 μg/ml; AUC：23.31 vs 10.63 μg.hr/ml（中位值））显著较高。然而，该组的Cmin-ss较低（0.80 vs 1.37 μg/ml），导致多次给药后磷司米霉素和克林霉素的血浆浓度波动显著较高（110.0 vs 41.9%）。其他药代动力学参数，特别是总清除率（CL/F）、表观分布容积（V/F、Vz/F）和消除半衰期（t1/2 z、t1/2 e）在两种给药方案之间也存在显著差异。此外，两组复发反应患者中，磷司米霉素和克林霉素的剂量依赖性药代动力学倾向于较低。研究结果可能表明，给药频率和持续时间对结局有显著影响。每6小时给药一次的磷司霉素（900 mg）和克林霉素（300-600 mg）联合给药至少5天，将构成治疗持续时间最短的最低剂量方案，其治愈率可超过95%。
This study investigated the pharmacokinetics of fosmidomycin when given in combination with clindamycin at two dosage regimens in patients with acute uncomplicated falciparum malaria. A total of 70 patients with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrolment criteria were recruited in the pharmacokinetic study. Patients were treated with two different dosage regimens of fosmidomycin in combination with clindamycin as follows: Group I: fosmidomycin (900 mg) and clindamycin (300 mg) every 6 hours for 3 days (n = 25); and Group II: fosmidomycin (1,800 mg) and clindamycin (600 mg) every 12 hours for 3 days (n = 54). Both regimens were well tolerated with no serious adverse events. The 28-day cure rates for Group I and Group II were 91.3 and 89.7%, respectively. Steady-state plasma concentrations of fosmidomycin and clindamycin were attained at about 24 hr after the first dose. The pharmacokinetics of both fosmidomycin and clindamycin analysed by model-independent and model-dependent approaches were generally in broad agreement. There were marked differences in the pharmacokinetic profiles of fosmidomycin and clindamycin when given as two different combination regimens. In general, most of the dose-dependent pharmacokinetic parameters (model-independent Cmax: 3.74 vs 2.41 μg/ml; Cmax-ss: 2.80 vs 2.08 μg/ml; Cmax-min-ss: 2.03 vs 0.71 μg/ml; AUC: 23.31 vs 10.63 μg.hr/ml (median values) were significantly higher in patients who received the high dose regimen (Group II). However, Cmin-ss was lower in this group (0.80 vs 1.37 μg/ml), resulting in significantly higher fluctuations in the plasma concentrations of both fosmidomycin and clindamycin following multiple dosing (110.0 vs 41.9%). Other pharmacokinetic parameters, notably total clearance (CL/F), apparent volume of distribution (V/F, Vz/F) and elimination half-life (t1/2z, t1/2e) were also significantly different between the two dosage regimens. In addition, the dose-dependent pharmacokinetics of both fosmidomycin and clindamycin tended to be lower in patients with recrudescence responses in both groups. The findings may suggest that dosing frequency and duration have a significant impact on outcome. The combination of fosmidomycin (900 mg) and clindamycin (300–600 mg) administered every six hours for a minimum of five days would constitute the lowest dose regimen with the shortest duration of treatment and which could result in a cure rate greater than 95%.
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影响因子：
4.9
作者：
NEU, HC;KAMIMURA, T
通讯作者：
KAMIMURA, T
影响因子：
3
作者：
Na-Bangchang K;Ruengweerayut R;Karbwang J;Chauemung A;Hutchinson D
通讯作者：
Hutchinson D
影响因子：
6.4
作者：
Borrmann, S;Adegnika, AA;Kremsner, PG
通讯作者：
Kremsner, PG
影响因子：
2.2
作者：
Cheoymang, Anurak;Hudchinton, David;Na-Bangchang, Kesara
通讯作者：
Na-Bangchang, Kesara
影响因子：
56.9
作者：
Jomaa, H;Wiesner, J;Beck, E
通讯作者：
Beck, E