Population pharmacokinetic analysis of high-dose methotrexate in pediatric and adult oncology patients

Cancer Chemother Pharmacol. 2019 Dec;84(6):1339-1348. doi: 10.1007/s00280-019-03966-4. Epub 2019 Oct 4.

Abstract

Purpose: High-dose methotrexate (HD-MTX) is widely used in pediatric and adult oncology treatment regimens. This study aimed to develop a population pharmacokinetic model to characterize pediatric and adult MTX exposure across various disease types and dosing regimens, and to evaluate exposure-toxicity relationships.

Methods: MTX pharmacokinetic data from pediatric and adult patients were collected. A population pharmacokinetic model was developed to determine the effects of age, liver function, renal function, and demographics on MTX disposition. The final model was used in Monte Carlo simulations to generate expected exposures for different dosing regimens. The association of toxicity, determined through chart review, and MTX area under the curve (AUC) was modeled using logistic regression.

Results: The analysis included 5116 MTX concentrations from 320 patients (135 adult, age 19-79 years; 185 pediatric, age 0.6-19 years). Estimated glomerular filtration rate (eGFR) and treatment cycle number were independent predictors of clearance (CL). CL varied 2.1-fold over the range of study eGFR values and increased 14% for treatment cycle numbers greater than 7. Higher MTX AUC was associated with higher risk of nephrotoxicity in adults, and neurotoxicity and hepatotoxicity in pediatrics.

Conclusions: This study represents one of the most comprehensive evaluations of HD-MTX PK across a wide range of ages and disease types. After accounting for differences in renal function, age did not impact CL, although toxicity patterns differed by age. The model allows for early identification of patients with slowed MTX clearance and at higher risk of toxicity.

Keywords: Methotrexate; Oncology; Pediatric; Population pharmacokinetic modeling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Antimetabolites, Antineoplastic / toxicity
  • Area Under Curve
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions / blood
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Drug-Related Side Effects and Adverse Reactions / prevention & control
  • Female
  • Glomerular Filtration Rate
  • Humans
  • Infant
  • Male
  • Metabolic Clearance Rate
  • Methotrexate / administration & dosage
  • Methotrexate / pharmacokinetics*
  • Methotrexate / toxicity
  • Middle Aged
  • Models, Biological*
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Young Adult

Substances

  • Antimetabolites, Antineoplastic
  • Methotrexate