Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria
Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria
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DOI：
10.1128/aac.44.3.697-704.2000
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发表时间：
2000-03-01
影响因子：
4.9
通讯作者：
White, NJ
中科院分区：
文献类型：
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作者：
Ezzet, F;van Vugt, M;White, NJ
本研究的目的是在对蒿甲醚-鲁芬净治疗单纯性多药耐药恶性疟疾的3种联合方案进行盲法比较时，对卢布芬进行前瞻性的人群药代动力学和药效学评价。266名泰国患者接受了3种联合方案，其中成人平均剂量3天1 920毫克(4剂)(方案A)或3天或5天2 780 mg(6剂)(方案B或C)。对51名住院成人进行了详细的观察，并在社区环境中收集了215名所有年龄段的患者的稀疏数据。鲁米芬的群体吸收半衰期为4.5h，模型血药浓度中位数(第5百分位数和第95百分位数)分别为6.2(0.25和14.8)mU g/ml，9.0(1.1和19.8)mU g/ml和8(1.4和17.4)mU g/ml。在急性疟疾期间，患者对药物的吸收分数有显著差异(变异系数为150%)。随着临床恢复，这一比例显著增加，变异性降低，这主要是因为食物摄取的恢复；服用正常膳食剂量给药使口服生物利用度增加了108%(90%可信区间，至164%)(P，0.0001)，高剂量方案(B和C)在浓度-时间曲线(AUC)下的面积分别增加了60%和100%，因此血药浓度超过体内推定MIC280mUg/ml的持续时间更长(方案B的中位数为252h；方案C的中位数为298h；方案A，204h[P，0.0001])和较高的治愈率。鲁米芬的口服生物利用度在很大程度上依赖于食物，因此在急性疟疾中很差，但随着康复而显着改善。两个六剂量方案的高治愈率是由于增加了AUC和延长了鲁米芬浓度超过体内MIC的时间。
The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria, Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h, The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) mu g/ml after regimen A, 9.0 (1.1 and 19.8) mu g/ml after regimen B, and 8 (1.4 and 17.4) mu g/ml after regimen C, During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal dose to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001), The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 mu g/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.