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

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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.

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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).

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Authors and Affiliations

  1. UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Sonoko Kawakatsu & Ila Saunders

  2. Division of Hematology-Oncology, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA

    Mina Nikanjam

  3. UCSF Benioff Children’s Hospital Oakland, 747 52nd Street, Oakland, CA, 94609, USA

    Mark Lin

  4. Department of Pharmacy, UCSD Health, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA

    Sonny Le

  5. Division of Pediatric Hematology-Oncology, University of California San Diego, La Jolla, CA, USA

    Dennis John Kuo

  6. Rady Children’s Hospital San Diego, 3020 Children’s Way MC 5035, San Diego, CA, 92123, USA

    Dennis John Kuo

  7. Division of Host-Microbe Systems and Therapeutics, University of California San Diego, 9500 Gilman Drive MC 0657, La Jolla, CA, 92093, USA

    Edmund V. Capparelli

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  1. Sonoko Kawakatsu
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Corresponding author

Correspondence to Edmund V. Capparelli.

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Conflict of interest

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

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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.

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Kawakatsu, S., Nikanjam, M., Lin, M. et al. Population pharmacokinetic analysis of high-dose methotrexate in pediatric and adult oncology patients. Cancer Chemother Pharmacol 84, 1339–1348 (2019). https://doi.org/10.1007/s00280-019-03966-4

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  • DOI: https://doi.org/10.1007/s00280-019-03966-4

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