Population pharmacokinetics of mefloquine in patients with acute falciparum malaria
Population pharmacokinetics of mefloquine in patients with acute falciparum malaria
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DOI：
10.1016/s0009-9236(99)70010-x
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发表时间：
1999-11-01
影响因子：
6.7
通讯作者：
White, NJ
中科院分区：
文献类型：
--
作者：
Simpson, JA;Price, R;White, NJ
目的：构建甲氟喹治疗恶性疟的群体药代动力学模型。背景：甲氟喹是耐多药恶性疟的首选治疗药物。影响甲氟喹在急性疟疾中药代动力学特性的因素尚未得到很好的表征。方法：采用非线性混合效应模型对 257 例急性恶性疟疾患者的甲氟喹药代动力学特性进行了评估。使用两种不同的口服剂量方案：(1) 初始剂量为 15 mg/kg，24 小时后剂量为 10 mg/kg (n = 159)；(2) 单剂量 25 mg/kg (n = 98)，105 名 (41%) 患者将甲氟喹与青蒿琥酯联合治疗（74 名患者接受分次剂量，31 名患者接受单剂量）。甲氟喹剂量使单药治疗的浓度-时间曲线下面积 [AUC(0-无穷大)] 增加 50%（95% 置信区间 [CI]，36% 至 65%），联合治疗增加 20%（95% CI，3% 至 40%）。与单剂量（平均 20.37 L/kg；95% CI，16.26 至 25.51 L/kg）相比，接受分次剂量甲氟喹单药治疗的患者（平均 8.14 L/kg；95% CI，7.49 至 8.86 L/kg）表观分布容积（V/F）显着较低，接受甲氟喹单药治疗并清除寄生虫血症的患者与寄生虫清除速度较慢的患者相比，在不到 48 小时内的 AUC（0-无穷大）显着较高，与任何混杂因素无关（几何平均值 [95% CI]，50,373 ng/mL.day [46,121 至 55,017 ng/mL.day] 与 45,583 ng/mL.day [42,306 至 49,125] ng/mL.day]），结论：甲氟喹在疟疾中的药代动力学特性相对不受人口统计变量（体重除外）或疾病严重程度的影响。如果假设表观清除率和分布容积不受剂量方案的影响，则分批25 mg/kg甲氟喹剂量可改善急性恶性疟疾的口服生物利用度和治疗反应。
Objective: To construct a population pharmacokinetic model for mefloquine in the treatment of falciparum malaria.Background: Mefloquine is the treatment of choice for multidrug-resistant falciparum malaria. The factors that influence the pharmacokinetic properties of mefloquine in acute malaria are not well characterized,Methods: The pharmacokinetic properties of mefloquine were evaluated in 257 patients with acute falciparum malaria by use of nonlinear mixed-effects modeling. Two different oral dose regimens were used: (1) a split dose of 15 mg base/kg initially followed by 10 mg/kg 24 hours later (n = 159) and (2) a single dose of 25 mg/kg (n = 98), Mefloquine was combined with artesunate in 105 (41%) patients (74 received a split dose and 31 received a single dose).Results: Splitting the mefloquine dose increased the area under the concentration-time curve [AUC(0-infinity)] by 50% (95% confidence interval [CI], 36% to 65%) for monotherapy and by 20% (95% CI, 3% to 40%) for combined therapy. The apparent volume of distribution (V/F) was significantly lower in patients receiving split doses of mefloquine monotherapy (mean, 8.14 L/kg; 95% CI, 7.49 to 8.86 L/kg) compared with a single dose (mean, 20.37 L/kg; 95% CI, 16.26 to 25.51 L/kg), Patients who received mefloquine monotherapy and cleared parasitemia in less than 48 hours had a significantly higher AUC(0-infinity) independent of any confounders, compared with patients with slower parasite clearance (geometric mean [95% CI], 50,373 ng/mL.day [46,121 to 55,017 ng/mL.day] versus 45,583 ng/mL.day [42,306 to 49,125 ng/mL.day]),Conclusions: The pharmacokinetic properties of mefloquine in malaria were relatively unaffected by demographic variables (other than body weight) or disease severity. Lf it is assumed that apparent clearance and volume of distribution are unaffected by dose regimen, then splitting the 25 mg/kg mefloquine dose improves oral bioavailability and the therapeutic response in the treatment of acute falciparum malaria.