Simpson J A, Price R, ter Kuile F, Teja-Isavatharm P, Nosten F, Chongsuphajaisiddhi T, Looareesuwan S, Aarons L, White N J
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Clin Pharmacol Ther. 1999 Nov;66(5):472-84. doi: 10.1016/S0009-9236(99)70010-X.
To construct a population pharmacokinetic model for mefloquine in the treatment of falciparum malaria.
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.
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).
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 x day [46,121 to 55,017 ng/mL x day] versus 45,583 ng/mL x day [42,306 to 49,125 ng/mL x day]).
The pharmacokinetic properties of mefloquine in malaria were relatively unaffected by demographic variables (other than body weight) or disease severity. If 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.
构建甲氟喹治疗恶性疟的群体药代动力学模型。
甲氟喹是耐多药恶性疟的治疗首选药物。影响甲氟喹在急性疟疾中药物动力学特性的因素尚未得到充分阐明。
采用非线性混合效应模型评估257例急性恶性疟患者中甲氟喹的药代动力学特性。使用了两种不同的口服给药方案：（1）初始剂量为15mg碱基/kg分服，24小时后再服10mg/kg（n = 159）；（2）单次剂量25mg/kg（n = 98）。105例（41%）患者中甲氟喹与青蒿琥酯联用（74例接受分服，31例接受单次剂量）。
对于单药治疗，分服甲氟喹剂量使浓度-时间曲线下面积[AUC(0-∞)]增加50%（95%置信区间[CI]，36%至65%），对于联合治疗增加20%（95%CI，3%至40%）。接受甲氟喹分服单药治疗的患者的表观分布容积（V/F）显著低于单次剂量组（均值，8.14L/kg；95%CI，7.49至8.86L/kg），单次剂量组均值为20.37L/kg（95%CI，16.26至25.51L/kg）。与寄生虫清除较慢的患者相比，接受甲氟喹单药治疗且在48小时内清除寄生虫血症的患者的AUC(0-∞)显著更高，且不受任何混杂因素影响（几何均值[95%CI]，50,373ng/mL·天[46,121至55,017ng/mL·天]对45,583ng/mL·天[42,306至49,125ng/mL·天]）。
疟疾中甲氟喹的药代动力学特性相对不受人口统计学变量（体重除外）或疾病严重程度的影响。如果假定表观清除率和分布容积不受给药方案影响，那么将25mg/kg甲氟喹剂量分服可提高口服生物利用度及急性恶性疟治疗中的治疗反应。
