Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma
ObjectiveMethotrexate (MTX) serves as a cornerstone therapy for primary central nervous system lymphoma (PCNSL). However, the considerable intra- and inter-individual variability in its pharmacokinetic and therapeutic efficacy poses significant challenges to clinical application. This study aims to...
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Frontiers Media S.A.
2025-05-01
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| author | Shifeng Wei Shifeng Wei Sitian Zhang Dan Wang Dan Wang Dongjie Zhang Qian Lu Jiayi Mo Jiayi Mo Zhilin Yang Zhilin Yang Leyi Guan Yingjun He Zhigang Zhao Zhigang Zhao Shenghui Mei Shenghui Mei |
| author_facet | Shifeng Wei Shifeng Wei Sitian Zhang Dan Wang Dan Wang Dongjie Zhang Qian Lu Jiayi Mo Jiayi Mo Zhilin Yang Zhilin Yang Leyi Guan Yingjun He Zhigang Zhao Zhigang Zhao Shenghui Mei Shenghui Mei |
| author_sort | Shifeng Wei |
| collection | DOAJ |
| description | ObjectiveMethotrexate (MTX) serves as a cornerstone therapy for primary central nervous system lymphoma (PCNSL). However, the considerable intra- and inter-individual variability in its pharmacokinetic and therapeutic efficacy poses significant challenges to clinical application. This study aims to employ population pharmacokinetic (PPK) models to investigate the pharmacokinetics of MTX in Chinese patients with PCNSL, thereby facilitating personalized therapeutic strategies for these patients.MethodA retrospective dataset comprising 6074 MTX plasma concentrations from 752 adult patients with PCNSL receiving high-dose methotrexate (HD-MTX) therapy was employed to construct the PPK model, utilizing the nonlinear mixed-effects modeling approach. The pharmacokinetics of MTX were characterized using a three-compartment model in conjunction with a proportional residual model. Covariate effects on model parameters were evaluated using forward addition and backward elimination approaches. Model performance was assessed through goodness-of-fit, bootstrap analysis, and visual predictive checks.ResultIn the final PPK models, the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and a combined genotype of ABCC-ABCG-ADORA2A were identified as significant covariates impacting the clearance (CL) of MTX. Additionally, total protein (TP) was found to be a significant covariate influencing inter-compartmental clearance (Q). The relationship between pharmacokinetic parameters and covariates was quantified as follows: CL (L/h) = 8.45×(eGFR⁄101.8)0.67×(BUN⁄4.6)−0.08×(ALT⁄25)0.03×a (a = 0.91 for gene-model if ABCC-ABCG-ADORA2A mutation, otherwise a = 1); Q1 (L/h) = 0.04×(TP⁄58)b (b = −1.68 for nongene-model and b = −1.72 for gene-model). Bootstrap analysis and visual predictive checks demonstrated the stability and adequate predictive capacity of the final PPK models.ConclusionIn managing HD-MTX therapy for PCNSL patients, it is essential to consider pharmacokinetic factors such as eGFR, BUN, ALT, TP, and genetic polymorphisms. The PPK models developed will aid in optimizing and personalizing HD-MTX treatment for PCNSL patients. |
| format | Article |
| id | doaj-art-c6545ae8d7de429c8e481df4561d95f9 |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-c6545ae8d7de429c8e481df4561d95f92025-08-20T02:32:11ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-05-011610.3389/fphar.2025.15780331578033Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphomaShifeng Wei0Shifeng Wei1Sitian Zhang2Dan Wang3Dan Wang4Dongjie Zhang5Qian Lu6Jiayi Mo7Jiayi Mo8Zhilin Yang9Zhilin Yang10Leyi Guan11Yingjun He12Zhigang Zhao13Zhigang Zhao14Shenghui Mei15Shenghui Mei16Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaSchool of Basic Medical Sciences, Capital Medical University, Beijing, ChinaDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Pharmacy, Bijie Maternal and Child Health Hospital, Bijie, Guizhou, ChinaDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaDepartment of Pharmacy, Bijie Maternal and Child Health Hospital, Bijie, Guizhou, ChinaDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaDepartment of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing, ChinaObjectiveMethotrexate (MTX) serves as a cornerstone therapy for primary central nervous system lymphoma (PCNSL). However, the considerable intra- and inter-individual variability in its pharmacokinetic and therapeutic efficacy poses significant challenges to clinical application. This study aims to employ population pharmacokinetic (PPK) models to investigate the pharmacokinetics of MTX in Chinese patients with PCNSL, thereby facilitating personalized therapeutic strategies for these patients.MethodA retrospective dataset comprising 6074 MTX plasma concentrations from 752 adult patients with PCNSL receiving high-dose methotrexate (HD-MTX) therapy was employed to construct the PPK model, utilizing the nonlinear mixed-effects modeling approach. The pharmacokinetics of MTX were characterized using a three-compartment model in conjunction with a proportional residual model. Covariate effects on model parameters were evaluated using forward addition and backward elimination approaches. Model performance was assessed through goodness-of-fit, bootstrap analysis, and visual predictive checks.ResultIn the final PPK models, the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and a combined genotype of ABCC-ABCG-ADORA2A were identified as significant covariates impacting the clearance (CL) of MTX. Additionally, total protein (TP) was found to be a significant covariate influencing inter-compartmental clearance (Q). The relationship between pharmacokinetic parameters and covariates was quantified as follows: CL (L/h) = 8.45×(eGFR⁄101.8)0.67×(BUN⁄4.6)−0.08×(ALT⁄25)0.03×a (a = 0.91 for gene-model if ABCC-ABCG-ADORA2A mutation, otherwise a = 1); Q1 (L/h) = 0.04×(TP⁄58)b (b = −1.68 for nongene-model and b = −1.72 for gene-model). Bootstrap analysis and visual predictive checks demonstrated the stability and adequate predictive capacity of the final PPK models.ConclusionIn managing HD-MTX therapy for PCNSL patients, it is essential to consider pharmacokinetic factors such as eGFR, BUN, ALT, TP, and genetic polymorphisms. The PPK models developed will aid in optimizing and personalizing HD-MTX treatment for PCNSL patients.https://www.frontiersin.org/articles/10.3389/fphar.2025.1578033/fullmethotrexateprimary central nervous system lymphomapopulation pharmacokinetic modelnonlinear mixed-effects modelingestimated glomerular filtration rateblood urea nitrogen |
| spellingShingle | Shifeng Wei Shifeng Wei Sitian Zhang Dan Wang Dan Wang Dongjie Zhang Qian Lu Jiayi Mo Jiayi Mo Zhilin Yang Zhilin Yang Leyi Guan Yingjun He Zhigang Zhao Zhigang Zhao Shenghui Mei Shenghui Mei Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma Frontiers in Pharmacology methotrexate primary central nervous system lymphoma population pharmacokinetic model nonlinear mixed-effects modeling estimated glomerular filtration rate blood urea nitrogen |
| title | Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma |
| title_full | Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma |
| title_fullStr | Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma |
| title_full_unstemmed | Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma |
| title_short | Population pharmacokinetics of high-dose methotrexate in patients with primary central nervous system lymphoma |
| title_sort | population pharmacokinetics of high dose methotrexate in patients with primary central nervous system lymphoma |
| topic | methotrexate primary central nervous system lymphoma population pharmacokinetic model nonlinear mixed-effects modeling estimated glomerular filtration rate blood urea nitrogen |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1578033/full |
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