Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.
Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.
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DOI：
10.1007/s40262-018-0658-1
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发表时间：
2019-01
影响因子：
4.5
通讯作者：
Standing JF
中科院分区：
文献类型：
--
作者：
Boonsathorn S;Cheng I;Kloprogge F;Alonso C;Lee C;Doncheva B;Booth J;Chiesa R;Irwin A;Standing JF
本研究的目的是调查泊沙康唑在免疫功能低下儿童中的群体药代动力学，评估患者特征对泊沙康唑暴露的影响，并进行模拟以推荐最佳起始剂量。接受治疗药物监测的儿科患者的泊沙康唑血浆浓度是从三级儿科医院数据库中提取的。这些与从电子资源和案例笔记评论中收集的协变量合并。开发了异速缩放的群体药代动力学模型，以研究片剂和混悬剂相对生物利用度、混悬剂的非线性生物利用度的影响，然后进行逐步协变量模型构建练习，以确定其他重要的变异来源。从 117 名 5 个月至 18 岁的儿童中总共采集了 338 个泊沙康唑血浆浓度样本。使用单室模型，将片剂表观清除率标准化为 70 公斤体重的个体 15 L/h。发现混悬剂的生物利用度随着剂量的增加而降低；产生一半片剂生物利用度的估计悬浮剂量为 99 mg/m2。腹泻和质子泵抑制剂也与悬浮液生物利用度降低有关。在迄今为止最大规模的儿童群体药代动力学研究中，我们发现了与成人相似的协变量效应，但腹泻患者或同时服用质子泵抑制剂的患者中悬浮液的生物利用度较低，这可能特别限制了泊沙康唑在这些患者中的使用。本文的在线版本 (10.1007/s40262-018-0658-1) 包含补充材料，可供授权用户使用。
The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients. The online version of this article (10.1007/s40262-018-0658-1) contains supplementary material, which is available to authorized users.
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影响因子：
4.9
作者：
Kohl, V.;Mueller, C.;Rueping, M. J. G. T.
通讯作者：
Rueping, M. J. G. T.
影响因子：
6.1
作者：
Lindbom, L;Pihlgren, P;Jonsson, N
通讯作者：
Jonsson, N
影响因子：
4.9
作者：
Durani, Urshila;Tosh, Pritish K.;Tande, Aaron J.
通讯作者：
Tande, Aaron J.
影响因子：
2.3
作者：
Moton, Allen;Ma, Lei;McLeod, James
通讯作者：
McLeod, James
影响因子：
20.3
作者：
Marr, KA;Carter, RA;Corey, L
通讯作者：
Corey, L