Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.
Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.
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DOI：
10.1093/jac/dkac389
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发表时间：
2022-12-23
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影响因子：
--
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单次、高剂量脂质体阿替西汀B（LAm B; AmBisome，吉利德Sciences）与其他抗真菌药联合使用，在避免HIV相关隐球菌脑膜炎的全因死亡率方面，已证明非劣效于阿替西汀B脱氧胆酸盐。AmBisome的药代动力学（PK）数据有限。本研究的目的是描述AmBisome的群体PK，并对现有研究进行荟萃分析，以建议隐球菌脑膜脑炎的最佳剂量。将来自高剂量、短程AmBisome治疗隐球菌脑膜脑炎的II期和III期试验的数据合并，以开发群体PK模型。对AmBisome单药治疗试验进行了检索，并对临床结局数据进行了荟萃分析。具有药物从中央室的一级清除率的二室模型最佳拟合了数据，并能够量化PK的个体间变异程度。平均（SD）群体PK参数估计值为：清除率0.416（0.363）L/h;分布容积4.566（4.518）L;药物从中央室至外周室的一级转移为2.222（3.351）h−1，从外周室至中央室的一级转移为2.951（4.070）h−1。 荟萃分析的数据不足以表明AmBisome治疗隐球菌脑膜脑炎的最佳剂量。本研究提供了对AmBisome在群体水平的PK及其变异性的新见解。我们的分析还通过证明与事后PK/PD分析相关的挑战，强调了AmBisome药效学（PD）可用数据的缺乏，并强调了在开发新型抗真菌药物时进行全面和详细的PK/PD分析的重要性。
Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363) L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351) h−1, and from peripheral to central compartment 2.951 (4.070) h−1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.
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影响因子：
2.5
作者：
Lawrence DS;Youssouf N;Molloy SF;Alanio A;Alufandika M;Boulware DR;Boyer-Chammard T;Chen T;Dromer F;Hlupeni A;Hope W;Hosseinipour MC;Kanyama C;Lortholary O;Loyse A;Meya DB;Mosepele M;Muzoora C;Mwandumba HC;Ndhlovu CE;Niessen L;Schutz C;Stott KE;Wang D;Lalloo DG;Meintjes G;Jaffar S;Harrison TS;Jarvis JN
通讯作者：
Jarvis JN
影响因子：
4.9
作者：
Lestner, Jodi M.;Groll, Andreas H.;Hope, William W.
通讯作者：
Hope, William W.
影响因子：
3.8
作者：
Leenders, ACAP;Reiss, P;deMarie, S
通讯作者：
deMarie, S
影响因子：
4.9
作者：
Lestner, Jodi;McEntee, Laura;Hope, William
通讯作者：
Hope, William
DOI：
10.1016/0005-2736(84)90135-4
发表时间：
1984-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
MEHTA, R;LOPEZBERESTEIN, G;JULIANO, RL
通讯作者：
JULIANO, RL