Purpose: To characterize the population pharmacokinetics of cyclophosphamide, active 4-hydroxy-cyclophosphamide (4OH-CTX), and inactive carboxyethylphosphoramide mustard (CEPM), and their associations with hematologic toxicities in infants and young children with brain tumors. To use this information to provide cyclophosphamide dosing recommendations in this population. Patients and Methods: Patients received four cycles of a 1-hour infusion of 1.5 g/m2 cyclophosphamide. Serial samples were collected to measure cyclophosphamide, 4OH-CTX, and CEPM plasma concentrations. Population pharmacokinetic modeling was performed to identify the patient characteristics influencing drug disposition. Associations between drug exposures and metrics reflecting drug-induced neutropenia, erythropenia, and thrombocytopenia were investigated. A Bayesian approach was developed to predict 4OH-CTX exposure using only cyclophosphamide and CEPM plasma concentrations. Results: Data from 171 patients (0.07–4.9 years) were adequately fitted by a two-compartment (cyclophosphamide) and one-compartment model (metabolites). Young infants (<6 months) exhibited higher mean 4OH-CTX exposure than did young children (138.4 vs. 107.2 μmol/L·h, P < 0.0001). No genotypes exhibited clinically significant influence on drug exposures. Worse toxicity metrics were significantly associated with higher 4OH-CTX exposures. Dosing simulations suggested decreased cyclophosphamide dosage to 1.2 g/m2 for young infants versus 1.5 g/m2 for children to attain similar 4OH-CTX exposure. Bayesian-modeled 4OH-CTX exposure predictions were precise (mean absolute prediction error 14.8% ± 4.2%) and had low bias (mean prediction error 4.9% ± 5.1%). Conclusions: A 4OH-CTX exposure–toxicity association was established, and a decreased cyclophosphamide dosage for young infants was suggested to reduce toxicity in this population. Bayesian modeling to predict 4OH-CTX exposure may reduce clinical processing–related costs and provide insights into further exposure–response associations. This article is featured in Highlights of This Issue, [p. 1533][1] [1]: /lookup/volpage/26/1533?iss=7

中文翻译：

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环磷酰胺及其代谢物在原发性脑肿瘤的婴幼儿中的暴露-毒性关联：剂量的意义

目的：表征环磷酰胺，活性4-羟基-环磷酰胺（4OH-CTX）和无活性羧乙基磷酰胺芥末（CEPM）的总体药代动力学，以及它们与患有脑肿瘤的婴幼儿的血液学毒性的关系。要使用此信息为该人群提供环磷酰胺剂量建议。患者和方法：患者接受1小时1.5 g / m2环磷酰胺输注的四个周期。收集系列样品以测量环磷酰胺，4OH-CTX和CEPM血浆浓度。进行群体药代动力学建模以鉴定影响药物处置的患者特征。研究了药物暴露与反映药物诱导的中性粒细胞减少，红血球减少和血小板减少症的指标之间的关联。开发了一种贝叶斯方法，仅使用环磷酰胺和CEPM血浆浓度来预测4OH-CTX暴露。结果：采用两室（环磷酰胺）和单室（代谢物）模型对171例患者（0.07-4.9岁）的数据进行了充分拟合。幼儿（<6个月）比幼儿有更高的平均4OH-CTX暴露水平（138.4 vs. 107.2μmol/ L·h，P <0.0001）。没有基因型对药物暴露表现出临床上显着的影响。较差的毒性指标与较高的4OH-CTX暴露量显着相关。剂量模拟表明，要达到相似的4OH-CTX暴露水平，幼儿应将环磷酰胺剂量降低至1.2 g / m2，而儿童应降低至1.5 g / m2。贝叶斯模型的4OH-CTX暴露预测是精确的（平均绝对预测误差为14.8％±4。2％）并具有低偏差（平均预测误差4.9％±5.1％）。结论：建立了4OH-CTX暴露与毒性的关系，并建议减少婴幼儿的环磷酰胺剂量以减少该人群的毒性。用于预测4OH-CTX暴露的贝叶斯模型可以减少与临床处理相关的成本，并提供进一步的暴露与反应关联的见解。本文在本期要点[p。1533] [1] [1]：/ lookup / volpage / 26/1533？iss = 7 用于预测4OH-CTX暴露的贝叶斯模型可以减少与临床处理相关的成本，并提供进一步的暴露与反应关联的见解。本文在本期要点[p。1533] [1] [1]：/ lookup / volpage / 26/1533？iss = 7 用于预测4OH-CTX暴露的贝叶斯模型可以减少与临床处理相关的成本，并提供进一步的暴露与反应关联的见解。本文在本期要点[p。1533] [1] [1]：/ lookup / volpage / 26/1533？iss = 7