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