Abstract：
OBJECTIVE: Methotrexate is widely utilized in the chemotherapy of malignant tumors and autoimmune diseases in the pediatric population, but dosing can be challenging. Several population pharmacokinetic models were developed to characterize factors influencing variability and improve individualization of dosing regimens. However, significant covariates included varied across studies. The primary objective of this review was to summarize and discuss population pharmacokinetic models of methotrexate and covariates that influence pharmacokinetic variability in pediatric patients.
METHODS: Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed.
RESULTS: Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models.
CONCLUSIONS: A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification.
METHODS: Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed.
RESULTS: Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models.
CONCLUSIONS: A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification.
摘要：
目的：甲氨蝶呤广泛应用于儿科恶性肿瘤和自身免疫性疾病的化疗，但剂量可能是具有挑战性的。开发了几种群体药代动力学模型来表征影响变异性的因素并改善给药方案的个性化。然而,包括不同研究的重要协变量。这篇综述的主要目的是总结和讨论影响儿科患者药代动力学变异性的甲氨蝶呤和协变量的群体药代动力学模型。
方法：系统检索自成立至2023年7月7日在PubMed和EMBASE数据库中进行。报告质量是根据31个项目的清单进行评估的。提取了模型构建和验证的研究特征和信息，总结,并讨论。
结果：本研究纳入了18项研究（4项前瞻性研究和14项回顾性研究，样本量为14至772名患者，每名患者2.7至93.1个样本）。两室模型是甲氨蝶呤常用的结构模型，甲氨蝶呤的清除率范围为2.32至19.03L/h（中位数：6.86L/h）。发现体型和肾功能显着影响小儿患者甲氨蝶呤的清除率。关于其他协变量的作用的报告有限，如基因多态性和联合用药，在甲氨蝶呤儿科患者的药代动力学参数中。内部和外部评估用于评估群体药代动力学模型的性能。
结论：在常规临床使用前需要进行更严格的外部评估，以选择合适的PopPK模型。需要进一步的研究来纳入特定易感儿科人群的更大的队列或池分析，以提高对预测暴露谱和协变量识别的理解。
方法：系统检索自成立至2023年7月7日在PubMed和EMBASE数据库中进行。报告质量是根据31个项目的清单进行评估的。提取了模型构建和验证的研究特征和信息，总结,并讨论。
结果：本研究纳入了18项研究（4项前瞻性研究和14项回顾性研究，样本量为14至772名患者，每名患者2.7至93.1个样本）。两室模型是甲氨蝶呤常用的结构模型，甲氨蝶呤的清除率范围为2.32至19.03L/h（中位数：6.86L/h）。发现体型和肾功能显着影响小儿患者甲氨蝶呤的清除率。关于其他协变量的作用的报告有限，如基因多态性和联合用药，在甲氨蝶呤儿科患者的药代动力学参数中。内部和外部评估用于评估群体药代动力学模型的性能。
结论：在常规临床使用前需要进行更严格的外部评估，以选择合适的PopPK模型。需要进一步的研究来纳入特定易感儿科人群的更大的队列或池分析，以提高对预测暴露谱和协变量识别的理解。
