Assessing Dose-Exposure-Response Relationships of Miltefosine in Adults and Children using Physiologically-Based Pharmacokinetic Modeling Approach.
Assessing Dose-Exposure-Response Relationships of Miltefosine in Adults and Children using Physiologically-Based Pharmacokinetic Modeling Approach.
复制标题
DOI：
10.1007/s11095-023-03610-0
复制
发表时间：
2023-12
影响因子：
3.7
通讯作者：
Li, Mingzhong
中科院分区：
文献类型：
--
作者：
Madu, Shadrack J.;Wang, Ke;Chirumamilla, Siri Kalyan;Turner, David B.;Steel, Patrick G.;Li, Mingzhong
米替福辛是第一个也是唯一一个被成功用作抗利什曼病药物的口服药物。然而，该药物与不同人群（例如人群）的暴露模式和治愈率差异有关。临床试验中的种族和年龄（即儿童与成人）。在这项工作中，开发了基于群体生理学的机械药代动力学 (PBPK) 模型，用于在计算机临床试验中研究米替福辛的剂量-暴露-反应关系，并评估人群（特别是儿童和成人）之间的差异。 Simcyp 群体药代动力学平台用于预测虚拟群体中不同给药方案下血浆和外周血单核细胞 (PBMC) 中米替福辛的暴露量。模拟的治愈率基于虚拟人群中 AUCd0-28 > 535 µg⋅day/mL 的个体虚拟受试者数量的百分比。结果表明，可以建立成人和儿童的米替福辛PBPK模型来准确预测临床试验的PK数据。在相同剂量方案下，不同模拟种族的米替福辛治疗的预测剂量-暴露-反应没有显着差异，剂量选择策略决定了米替福辛治疗的临床结果。预计儿科中米替福辛治疗的治愈率较低，因为与接受相同剂量治疗的成人虚拟人群相比，虚拟儿科中模拟的米替福辛暴露量较低。机制 PBPK 模型表明，血浆中未结合的米替福辛的比例较高，是导致儿科失败概率较高的原因，因为成人和儿科之间血浆蛋白的分布存在差异。开发的 PBPK 模型可用于确定未来临床试验中的最佳米替福辛剂量方案。在线版本包含可在 10.1007/s11095-023-03610-0 获取的补充材料。
Miltefosine is the first and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with differences in exposure patterns and cure rates among different population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure–response relationship of miltefosine in in silico clinical trials and evaluate the differences in population groups, particularly children and adults. The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under different dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUCd0-28 > 535 µg⋅day/mL in the virtual population. It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no significant difference in the predicted dose-exposure–response of the miltefosine treatment for different simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment. The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the difference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials. The online version contains supplementary material available at 10.1007/s11095-023-03610-0.
登录
查看更多内容
影响因子：
3.7
作者：
Ostyn B;Hasker E;Dorlo TP;Rijal S;Sundar S;Dujardin JC;Boelaert M
通讯作者：
Boelaert M
在东非儿童中治疗内脏利什曼病治疗的同量米尔特福赛方案的药代动力学，安全性和功效：一项开放标签的II期临床试验。
DOI：
10.1093/cid/ciy747
发表时间：
2019-04-24
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Mbui J;Olobo J;Omollo R;Solomos A;Kip AE;Kirigi G;Sagaki P;Kimutai R;Were L;Omollo T;Egondi TW;Wasunna M;Alvar J;Dorlo TPC;Alves F
通讯作者：
Alves F
影响因子：
4.5
作者：
Maharaj AR;Gonzalez D;Cohen-Wolkowiez M;Hornik CP;Edginton AN
通讯作者：
Edginton AN
影响因子：
3.5
作者：
Abduljalil, K;Edwards, D;Barnett, A;Rose, R H;Cain, T;Jamei, M
通讯作者：
Jamei, M
影响因子：
3.8
作者：
Hall, Amy V.;Gostick, Isobel E. F.;Yufit, Dmitry S.;Marchant, Gloria Y.;Kirubakaran, Preyanthiny;Madu, Shadrack J.;Li, Mingzhong;Steel, Patrick G.;Steed, Jonathan W.
通讯作者：
Steed, Jonathan W.