Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.
Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.
复制标题
基于生理学的儿童甲氧苄啶和磺胺甲恶唑药代动力学模型。
DOI：
10.1007/s40262-018-00733-1
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发表时间：
2019
影响因子：
4.5
通讯作者：
Cohen-Wolkowiez,Michael
中科院分区：
文献类型：
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作者：
Thompson,ElizabethJ;Wu,Huali;Maharaj,Anil;Edginton,AndreaN;Balevic,StephenJ;Cobbaert,Marjan;Cunningham,AnthonyP;Hornik,ChristophP;Cohen-Wolkowiez,Michael
本研究的目的是（1）确定机会性收集的数据是否可用于开发儿科患者的生理学药代动力学（PBPK）模型;和（2）描述肾消除和肝代谢抗生素甲氧苄啶（TMP）-磺胺甲恶唑（SMX）药物处置的年龄相关性成熟变化方法我们在口服TMP-SMX组合产品后开发了TMP和SMX在儿童中的单独群体PBPK模型，并使用稀疏和机会性收集的血浆浓度样品来验证我们的儿科模型。我们根据观察到的90%预测区间之外的儿科数据数量评估了儿科PBPK模型的可预测性。我们对靶器官和组织（皮肤）浓度大于耐甲氧西林金黄色葡萄球菌（MRSA）最低抑菌浓度的情况进行了剂量模拟TMP 2 mg/L; SMX 9.5 mg/L）至少50%的给药间隔。结果我们发现TMP和SMX的观察数据分别为67-87%和71-91%，在五个年龄组的90%预测区间内捕获，表明我们的模型足够拟合。我们的模型重新推导的最佳剂量的TMP在靶组织的范围内的建议剂量为TMP-SMX在所有年龄组的儿童由目前的指导方针为治疗MRSA.ConclusionWe成功地开发了一个儿科PBPK模型的组合抗生素TMP-SMX使用稀疏和机会儿科药代动力学样本。这种新颖有效的方法有可能扩大PBPK建模在儿科药物开发中的应用。
ObjectiveThe aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metabolized antibiotic trimethoprim (TMP)–sulfamethoxazole (SMX).MethodsWe developed separate population PBPK models for TMP and SMX in children after oral administration of the combined TMP–SMX product and used sparse and opportunistically collected plasma concentration samples to validate our pediatric model. We evaluated predictability of the pediatric PBPK model based on the number of observed pediatric data out of the 90% prediction interval. We performed dosing simulations to target organ and tissue (skin) concentrations greater than the methicillin-resistantStaphylococcus aureus(MRSA) minimum inhibitory concentration (TMP 2 mg/L; SMX 9.5 mg/L) for at least 50% of the dosing interval.ResultsWe found 67–87% and 71–91% of the observed data for TMP and SMX, respectively, were captured within the 90% prediction interval across five age groups, suggesting adequate fit of our model. Our model-rederived optimal dosing of TMP at the target tissue was in the range of recommended dosing for TMP–SMX in children in all age groups by current guidelines for the treatment of MRSA.ConclusionWe successfully developed a pediatric PBPK model of the combination antibiotic TMP–SMX using sparse and opportunistic pediatric pharmacokinetic samples. This novel and efficient approach has the potential to expand the use of PBPK modeling in pediatric drug development.
影响因子：
11.2
作者：
R. Taetle;J. Castagnola;J. Mendelsohn
通讯作者：
R. Taetle;J. Castagnola;J. Mendelsohn
通过与铁螯合剂去铁胺和抗转铁蛋白受体的免疫球蛋白 G 单克隆抗体联合治疗，在体外协同抑制淋巴肿瘤生长。
影响因子：
20.3
作者：
Kemp,JD;Smith,KM;Kanner,LJ;Gomez,F;Thorson,JA;Naumann,PW
通讯作者：
Naumann,PW