Population Pharmacokinetic Study and Individual Dose Adjustments of High-Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia or Osteosarcoma.

IF 2.9 4区 医学 Journal of Clinical Pharmacology Pub Date : 2019-04-01 Epub Date: 2018-12-17 DOI:10.1002/jcph.1349
Ka Ho Hui, Ho Man Chu, Pui Shan Fong, Wai Tsoi Frankie Cheng, Tai Ning Lam
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引用次数: 26

Abstract

High-dose methotrexate (>0.5 g/m2 ) is among the first-line chemotherapeutic agents used in treating acute lymphoblastic leukemia (ALL) and osteosarcoma in children. Despite rapid hydration, leucovorin rescue, and routine therapeutic drug monitoring, severe toxicity is not uncommon. This study aimed at developing population pharmacokinetic (popPK) models of high-dose methotrexate for ALL and osteosarcoma and demonstrating the possibility and convenience of popPK model-based individual dose optimization using R and shiny, which is more accessible, efficient, and clinician-friendly than NONMEM. The final data set consists of 36 ALL (354 observations) and 16 osteosarcoma (585 observations) patients. Covariate model building and parameter estimations were done using NONMEM and Perl-speaks-NONMEM. Diagnostic Plots and bootstrapping validated the models' performance and stability. The dose optimizer developed based on the validated models can obtain identical individual parameter estimates as NONMEM. Compared to calling a NONMEM execution and reading its output, estimating individual parameters within R reduces the execution time from 8.7-12.8 seconds to 0.4-1.0 second. For each subject, the dose optimizer can recommend (1) an individualized optimal dose and (2) an individualized range of doses. For osteosarcoma, recommended optimal doses by the optimizer resemble the final doses at which the subjects were eventually stabilized. The dose optimizers developed demonstrated the potential to inform dose adjustments using a model-based, convenient, and efficient tool for high-dose methotrexate. Although the dose optimizer is not meant to replace clinical judgment, it provides the clinician with the individual pharmacokinetics perspective by recommending the (range of) optimal dose.

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中国儿童急性淋巴细胞白血病或骨肉瘤患者高剂量甲氨蝶呤的人群药动学研究及个体剂量调整。
大剂量甲氨蝶呤(>0.5 g/m2)是治疗儿童急性淋巴细胞白血病(ALL)和骨肉瘤的一线化疗药物之一。尽管快速补水,亚钙素救援和常规治疗药物监测,严重的毒性并不罕见。本研究旨在建立大剂量甲氨蝶呤治疗ALL和骨肉瘤的群体药代动力学(popPK)模型,并利用R和shiny证明基于popPK模型的个体剂量优化的可能性和方便性,该模型比NONMEM更容易获得、更高效、更临床友好。最终的数据集包括36例ALL(354例观察)和16例骨肉瘤(585例观察)患者。使用NONMEM和Perl-speaks-NONMEM进行协变量模型构建和参数估计。诊断图和自举验证了模型的性能和稳定性。基于验证模型开发的剂量优化器可以获得与NONMEM相同的单个参数估计。与调用NONMEM执行并读取其输出相比,在R中估计单个参数将执行时间从8.7-12.8秒减少到0.4-1.0秒。对于每个受试者,剂量优化器可以推荐(1)个体化最佳剂量和(2)个体化剂量范围。对于骨肉瘤,优化器推荐的最佳剂量与受试者最终稳定的最终剂量相似。开发的剂量优化器展示了使用基于模型的、方便和有效的高剂量甲氨蝶呤工具进行剂量调整的潜力。虽然剂量优化器并不意味着取代临床判断,但它通过推荐最佳剂量(范围)为临床医生提供个体药代动力学视角。
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来源期刊
Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
自引率
3.40%
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期刊介绍: The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.
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