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A population pharmacokinetic model of methotrexate in Korean patients with haematologic malignancy

Authors
 Yun Seob Jung  ;  Mijeong Son  ;  Sang-Guk Lee  ;  June-Won Chong  ;  Soo-Jeong Kim  ;  Ji Eun Jang  ;  Chuhl Joo Lyu  ;  Seung Min Hahn  ;  Jung Woo Han  ;  Kyungsoo Park 
Citation
 BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol.90(3) : 849-862, 2024-03 
Journal Title
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
ISSN
 0306-5251 
Issue Date
2024-03
MeSH
Adolescent ; Hematologic Neoplasms* / drug therapy ; Humans ; Methotrexate* / pharmacokinetics ; Methotrexate* / therapeutic use ; Models, Biological ; Republic of Korea ; Retrospective Studies
Keywords
NONMEM ; allometry ; covariates ; methotrexate ; population pharmacokinetics
Abstract
AimsThis study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with haematologic malignancy, identify factors affecting methotrexate PK, and propose an optimal dosage regimen for the Korean population.MethodsData were retrospectively collected from 188 patients with acute leukaemia or non-Hodgkin's lymphoma who were admitted to Severance Hospital during the period from November 2005 to January 2016. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model.ResultsA two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.09 L for central volume of distribution (V1$$ {\mathrm{V}}_1 $$), 17.65 L for peripheral volume of distribution (V2$$ {\mathrm{V}}_2 $$), 12.89 L/h for clearance (CL) and 0.655 L/h for inter-compartmental clearance in a 50 kg patient. Covariate analyses showed that, at the weight of 50 kg, CL decreased by 0.11 L/h for each 1-year increase in age above 14 years old and decreased 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (= V1$$ {\mathrm{V}}_1 $$ + V2$$ {\mathrm{V}}_2 $$) was 0.85 L/kg, which was similar to those in the Western or Chinese populations. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen.ConclusionsThe population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with haematologic malignancy.
Full Text
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15969
DOI
37984417
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Soo Jeong(김수정) ORCID logo https://orcid.org/0000-0001-8859-3573
Park, Kyungsoo(박경수) ORCID logo https://orcid.org/0000-0002-6972-1143
Lyu, Chuhl Joo(유철주) ORCID logo https://orcid.org/0000-0001-7124-7818
Lee, Sang-Guk(이상국) ORCID logo https://orcid.org/0000-0003-3862-3660
Jang, Ji Eun(장지은) ORCID logo https://orcid.org/0000-0001-8832-1412
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Hahn, Seung Min(한승민) ORCID logo https://orcid.org/0000-0001-9832-6380
Han, Jung Woo(한정우) ORCID logo https://orcid.org/0000-0001-8936-1205
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/200464
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