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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1339–1348 | Cite as

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

  • Sonoko Kawakatsu
  • Mina Nikanjam
  • Mark Lin
  • Sonny Le
  • Ila Saunders
  • Dennis John Kuo
  • Edmund V. CapparelliEmail author
Original Article
  • 155 Downloads

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 Pediatric Population pharmacokinetic modeling Oncology 

Notes

Acknowledgements

The authors would like to thank Dr. Sam Martinez, Dr. Jeremiah Momper, Dr. Lawrence Alejandro, and Dr. Don Barkauskas for help with the project. Funding support was provided by a Research in Pediatric and Developmental Pharmacology NIH grant (1U54HD090259-01, Dr. Capparelli).

Compliance with ethical standards

Conflict of interest

Dr. Capparelli serves on the data safety and monitoring board for Melinta Pharmaceuticals, Cempra Pharmaceuticals and The Medicines Company.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

280_2019_3966_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (PDF 1229 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sonoko Kawakatsu
    • 1
  • Mina Nikanjam
    • 2
  • Mark Lin
    • 3
  • Sonny Le
    • 4
  • Ila Saunders
    • 1
  • Dennis John Kuo
    • 5
    • 6
  • Edmund V. Capparelli
    • 7
    Email author
  1. 1.UC San Diego Skaggs School of Pharmacy and Pharmaceutical SciencesLa JollaUSA
  2. 2.Division of Hematology-OncologyUniversity of California San DiegoLa JollaUSA
  3. 3.UCSF Benioff Children’s Hospital OaklandOaklandUSA
  4. 4.Department of PharmacyUCSD HealthLa JollaUSA
  5. 5.Division of Pediatric Hematology-OncologyUniversity of California San DiegoLa JollaUSA
  6. 6.Rady Children’s Hospital San DiegoSan DiegoUSA
  7. 7.Division of Host-Microbe Systems and TherapeuticsUniversity of California San DiegoLa JollaUSA

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