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Understanding Hemoglobin Contribution to High-dose Methotrexate Disposition - Population Pharmacokinetics in Pediatric Patients with Hematological Malignancies
Škorić, B., Jovanović, M., Kuzmanović, M., Miljković, B., & Vučićević, K. M. (2023). Understanding Hemoglobin Contribution to High-dose Methotrexate Disposition-Population Pharmacokinetics in Pediatric Patients with Hematological Malignancies.
Škorić, B., Jovanović, M., Kuzmanović, M., Miljković, B., & Vučićević, K. M. (2023). Understanding Hemoglobin Contribution to High-dose Methotrexate Disposition-Population Pharmacokinetics in Pediatric Patients with Hematological Malignancies.
Škorić, B., Jovanović, M., Kuzmanović, M., Miljković, B., & Vučićević, K. M. (2023). Understanding Hemoglobin Contribution to High-dose Methotrexate Disposition-Population Pharmacokinetics in Pediatric Patients with Hematological Malignancies.
Škorić, B., Jovanović, M., Kuzmanović, M., Miljković, B., & Vučićević, K. M. (2023). Understanding Hemoglobin Contribution to High-dose Methotrexate Disposition-Population Pharmacokinetics in Pediatric Patients with Hematological Malignancies.
Abstract
Aim was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) and to describe the sources of variability. The study included 50 patients (1-18 years) who received 3 or 5 g/m2 of HDMTX. Nonlinear mixed effects modeling approach was applied for data analysis. Parameter estimation was performed by FOCEI, whereas stepwise covariate modeling was used to assess variability factors. The final two-compartment model incorporates the effect of body weight using allometric scaling and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical 70 kg subject were: 11 L/h for clearance (CL), 46.5 L and 16.4 L for volume of central (V1) and peripheral compartment (V2), respectively, and 0.168 L/h for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 30% in MTX CL was observed among patients’ hemoglobin values reported in the study. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to HDMTX disposition.
Keywords
NONMEM; covariate analysis; PopPK; therapeutic drug monitoring; children.
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
