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Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters

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Abstract

Background and Objective

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice.

Methods

A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII®. A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics.

Results

Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively).

Conclusion

Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

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Author notes

  1. Ahmed Nader

    Present address: AbbVie, Inc, North Chicago, USA

Authors and Affiliations

  1. Qatar University College of Pharmacy, Doha, Qatar

    Ahmed Nader, Noran Zahran, Aya Alshammaa, Heba Altaweel & Kyle John Wilby

  2. Hamad Medical Corporation, Doha, Qatar

    Nancy Kassem

Authors
  1. Ahmed Nader
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  2. Noran Zahran
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  3. Aya Alshammaa
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  4. Heba Altaweel
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  5. Nancy Kassem
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Corresponding author

Correspondence to Ahmed Nader.

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Funding

This study was funded by a UREP award [UREP15-019-3-008] from the Qatar National Research Fund (a member of The Qatar Foundation).

Conflict of interest

Dr. Ahmed Nader, Noran Zahran, Aya Alshammaa, Heba Altaweel, Nancy Kassem and Dr. Kyle John Wilby have no conflicts of interest to disclose.

Ethical approval

All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments) and were approved by Qatar University and Hamad Medical Corporation institutional review boards.

Informed consent

No informed consent was required for this study given the study design (retrospective chart review) and the reporting of de-identified patient data.

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Nader, A., Zahran, N., Alshammaa, A. et al. Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters. Eur J Drug Metab Pharmacokinet 42, 221–228 (2017). https://doi.org/10.1007/s13318-016-0338-1

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  • DOI: https://doi.org/10.1007/s13318-016-0338-1

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