Population Pharmacokinetic and Toxicity Analysis of High-Dose Methotrexate in Patients with Central Nervous System Lymphoma.

in Clinical pharmacokinetics by Anyue Yin, Fleur A de Groot, Henk-Jan Guchelaar, Marcel Nijland, Jeanette K Doorduijn, Daan J Touw, Thijs Oude Munnink, Brenda C M de Winter, Lena E Friberg, Joost S P Vermaat, Dirk Jan A R Moes

TLDR

  • The study characterized the population pharmacokinetics of high-dose methotrexate in patients with central nervous system lymphoma and identified baseline predictors and exposure thresholds for nephro- and hepatotoxicity.

Abstract

High-dose methotrexate (HD-MTX)-based polychemotherapy is widely used for patients with central nervous system (CNS) lymphoma. The pharmacokinetic (PK) variability and unpredictable occurrence of toxicity remain major concerns in HD-MTX treatment. This study aimed to characterize the population PK of HD-MTX in patients with CNS lymphoma and to identify baseline predictors and exposure thresholds that predict a high risk of nephro- and hepatotoxicity. Routinely monitored serum MTX concentrations after intravenous infusion of HD-MTX and MTX dosing information were collected retrospectively. Acute event of toxicity (≥ grade 1) was defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on the basis of serum creatinine and alanine aminotransferase. A population PK model was developed in NONMEM. Toxicity data were analyzed using a logistic regression model, and potential baseline and exposure-related predictors were investigated. In total, 1584 MTX concentrations from 110 patients were available for analysis. A two-compartment population PK model adequately described the data. Estimated glomerular filtration rate (eGFR), treatment regimen, albumin, alkaline phosphatase, and body weight were identified as significant covariates that explain the PK variability of HD-MTX. Baseline eGFR and sex were identified as significant predictors for renal toxicity, and MTX dose (mg/m) was the strongest predictor for hepatotoxicity. The MTX area under the concentration-time curve (AUC) and concentration at 24 h (C) were shown to correlate with renal toxicity only, and 49,800 μg/L × h (109.6 μmol/L × h) and C> 3930 μg/L (8.65 μmol/L) were potential exposure thresholds predicting high risk (proportion > 60%). A population PK model was developed for HD-MTX in patients with CNS lymphoma. The toxicity analysis showed that lower baseline eGFR and male sex, and higher MTX dose are associated with increased risk of acute nephro- and hepatotoxicity, respectively. The proposed exposure thresholds that predict high risk of renal toxicity and the developed models hold the potential to guide HD-MTX dosage individualization and better prevent acute toxicity.

Overview

  • The study aimed to characterize the population pharmacokinetics of high-dose methotrexate (HD-MTX) in patients with central nervous system lymphoma and identify baseline predictors and exposure thresholds that predict high risk of nephro- and hepatotoxicity.
  • The study analyzed retrospectively collected serum methotrexate concentrations and dosing information from 110 patients. The data collected included estimated glomerular filtration rate (eGFR), treatment regimen, albumin, alkaline phosphatase, and body weight.
  • The study aimed to achieve a better understanding of the pharmacokinetic variability and predictivity of HD-MTX in patients with CNS lymphoma, which would guide dosage individualization and prevent acute toxicity.

Comparative Analysis & Findings

  • The population PK model developed in NONMEM adequately described the data. The model identified eGFR, treatment regimen, albumin, alkaline phosphatase, and body weight as significant covariates to explain the PK variability of HD-MTX.
  • The logistic regression analysis identified baseline eGFR and sex as significant predictors of renal toxicity, and MTX dose (mg/m) was the strongest predictor of hepatotoxicity.
  • The analysis showed that lower baseline eGFR and male sex were associated with increased risk of acute nephro-toxicity, while higher MTX dose was associated with increased risk of acute hepatotoxicity.

Implications and Future Directions

  • The proposed exposure thresholds (49,800 μg/L × h and C> 3930 μg/L) may guide HD-MTX dosage individualization and better prevent acute toxicity in patients with CNS lymphoma.
  • Future studies can build on this research by validating the developed models and exposure thresholds in prospective studies, exploring the potential for adjusting HD-MTX dosing based on individual patient characteristics.
  • Further investigation is needed to understand the impact of genetic and environmental factors on HD-MTX pharmacokinetics and to identify additional predictors of toxicity in patients with CNS lymphoma.
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