Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens
Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens
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DOI：
10.1128/aac.00933-12
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发表时间：
2012-10-01
影响因子：
4.9
通讯作者：
Stevens, David A.
中科院分区：
文献类型：
--
作者：
Hope, William W.;Goodwin, Joanne;Stevens, David A.
脂质体阿替霉素B的间歇方案越来越受到关注，这可能有助于在门诊环境中使用。然而，关于最合适的剂量和给药时间表知之甚少。从30例接受脂质体阿霉素B经验性治疗疑似侵袭性真菌感染的患者中获得血浆药代动力学数据。研究了两个队列。第一个队列接受3 mg脂质体阿替霉素B/kg体重/天;第二个队列在0时接受10 mg脂质体阿替霉素B/kg，随后在48和120 h接受5 mg/kg。通过高压液相色谱法（HPLC）测定脂质体阿替霉素B的水平。使用群体方法估计药代动力学。进行了Monte Carlo模拟。采用D-最优设计确定常规和间歇方案的最大信息采样时间，以供将来研究使用。三室药代动力学模型最好地描述了数据。常规和间歇给药的药代动力学均呈线性。清除率和中央室容积的平均值（标准差）估计值分别为1.60（0.85）L/h和20.61（15.27）L。Monte Carlo模拟显示药物暴露存在相当大的变异性。清除率和体积的贝叶斯估计值随体重线性增加，但只有前者具有统计学意义（P = 0.039）。D-最优设计为将来的药代动力学研究提供了最大信息量的采样时间。常规和间歇给药的高剂量方案脂质体阿替霉素B的药代动力学是线性的。需要进一步的药代动力学-药效学临床前和临床研究来确定安全有效的间歇治疗方案。
There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P = 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.