Population Pharmacokinetics of Posaconazole in Immune-Compromised Children and Assessment of Target Attainment in Invasive Fungal Disease.
Population Pharmacokinetics of Posaconazole in Immune-Compromised Children and Assessment of Target Attainment in Invasive Fungal Disease.
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免疫受损儿童中寄生虫的种群药代动力学以及对侵入性真菌疾病中目标成就的评估。
DOI：
10.1007/s40262-023-01254-2
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发表时间：
2023-07
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
泊沙康唑(PSZ)是一种三唑类抗真菌药物，用于治疗成人和儿童的侵袭性真菌病(IFD)。虽然PSZ有静脉(IV)溶液、口服混悬剂(OS)和延迟释放片(DRTS)，但OS是儿科使用的首选配方，因为IV配方中的赋形剂存在潜在的安全性问题，而且儿童难以吞咽完整的片剂。然而，OS制剂不良的生物药学特性导致儿童中PSZ的剂量-暴露曲线不可预测，有可能导致治疗失败。这项研究的目的是描述PSZ在免疫低下儿童中的群体药代动力学(PK)，并评估治疗目标的实现。PSZ的血药浓度是从住院患者的记录中回溯收集的。在NONMEM(v7.4)的非线性混合效应模型框架下进行群体PK分析。将PK参数与体重进行比对，然后评估潜在的协变量效应。最终的PK模型被用来通过使用Simulx(V2021R1)模拟目标实现(作为稳态谷浓度高于推荐目标的人口的百分比)来评估推荐的剂量方案。对47例1~21岁免疫功能低下患者静脉和/或口服PSZ的202个血药浓度进行了重复测量。具有一阶吸收和线性消除的一室PK模型最适合于该数据。混悬剂的绝对生物利用度(95%可信区间)为16%(8-27%)，显著低于报道的片剂生物利用度(Ft)[67%]。潘托拉唑(PAN)和奥美拉唑(OME)联合用药后FS分别减少62%和75%。法莫替丁仅使FS减少22%。当PAN或OME不与混悬剂同时给药时，固定剂量和基于重量的适应性剂量都能提供足够的目标达标率。这项研究的结果表明，固定和基于重量的适应性给药方案都适用于所有PSZ制剂(包括混悬剂)的目标实现。此外，协变量分析表明，在PSZ混悬剂剂量期间，应禁忌使用伴随的质子泵抑制剂。网上版载有补充材料，可在10.1007/s40262-023-01254-2查阅。
Posaconazole (PSZ) is a triazole antifungal for the management of invasive fungal disease (IFD) in adults and children. Although PSZ is available as an intravenous (IV) solution, oral suspension (OS) and delayed-release tablets (DRTs), OS is the preferred formulation for pediatric use because of potential safety concerns associated with an excipient in the IV formulation and difficulty in swallowing intact tablets by children. However, poor biopharmaceutical characteristics of the OS formulation leads to an unpredictable dose-exposure profile of PSZ in children, potentially risking therapeutic failure. The goal of this study was to characterize the population pharmacokinetics (PK) of PSZ in immunocompromised children and assess therapeutic target attainment. Serum concentrations of PSZ were collected retrospectively from records of hospitalized patients. A population PK analysis was performed in a nonlinear mixed-effects modeling framework with NONMEM (v7.4). The PK parameters were scaled to body weight, then potential covariate effects were assessed. The final PK model was used to evaluate recommended dosing schemes through simulation of target attainment (as a percentage of the population having steady-state trough concentrations above the recommended target) using Simulx (v2021R1). Repeated measurement data of 202 serum concentrations of total PSZ were acquired from 47 immunocompromised patients between 1 and 21 years of age receiving PSZ either intravenously or orally, or both. A one-compartment PK model with first-order absorption and linear elimination best fit the data. The estimated absolute bioavailability (95% confidence interval) for suspension (Fs) was 16% (8–27%), which was significantly lower than the reported tablet bioavailability (Ft) [67%]. Fs was reduced by 62% and 75% upon concomitant administration with pantoprazole (PAN) and omeprazole (OME), respectively. Famotidine resulted in a reduction of Fs by only 22%. Both fixed dosing and weight-based adaptive dosing provided adequate target attainment when PAN or OME were not coadministered with the suspension. The results of this study revealed that both fixed and weight-based adaptive dosing schemes can be appropriate for target attainment across all PSZ formulations, including suspension. Additionally, covariate analysis suggests that concomitant proton pump inhibitors should be contraindicated during PSZ suspension dosing. The online version contains supplementary material available at 10.1007/s40262-023-01254-2.
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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：
Comets, Emmanuelle;Brendel, Karl;Mentre, France
通讯作者：
Mentre, France
影响因子：
3.2
作者：
Pana, Zoi Dorothea;Roilides, Emmanuel;Zaoutis, Theoklis
通讯作者：
Zaoutis, Theoklis
DOI：
10.1016/j.ijantimicag.2020.106084
发表时间：
2020-09-01
影响因子：
10.8
作者：
Groll, Andreas H.;Abdel-Azim, Hisham;Bruno, Christopher J.
通讯作者：
Bruno, Christopher J.
影响因子：
5.6
作者：
Jia, Mengmeng;Zhang, Qiwen;Qin, Zifei;Wang, Dao;Liu, Peng;Yang, Jing;Zhang, Xiaojian
通讯作者：
Zhang, Xiaojian