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A Population Pharmacokinetic Model for Low-Dose Methotrexate and its Polyglutamated Metabolites in Red Blood Cells

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Abstract

Background

Measurement of intracellular concentrations of methotrexate (MTX) and its polyglutamated metabolites (MTXGlu2–5) in red blood cells (RBCs) has been suggested as a potential means of monitoring low-dose MTX treatment of rheumatoid arthritis (RA). However, a possible correlation between RBC MTX and MTXGlu2–5 concentrations and clinical outcomes of MTX treatment in RA is debated. A better understanding of the dose-concentration–time relationship of MTX and MTXGlu2–5 in RBCs by population pharmacokinetic modelling is desirable and will facilitate assessing a potential RBC concentration–effect relationship in the future.

Aim

The purpose of this analysis was to describe the pharmacokinetics of MTX and MTXGlu2–5 in RBCs. Secondary objectives included investigation of deglutamation reactions and the loss of MTX and MTXGlu2–5 from the RBC.

Methods

A model was developed using NONMEM® version 7.2 based on RBC data obtained from 48 patients with RA receiving once-weekly low-dose MTX treatment. This model was linked to a fixed two-compartment model that was used to describe the pharmacokinetics of MTX in the plasma. A series of five compartments were used to describe the intracellular pharmacokinetics of MTX and MTXGlu2–5 in RBCs. Biologically plausible covariates were tested for a significant effect on MTX plasma clearance and the intracellular volume of distribution of all MTX species in RBCs (\({V}_{\text{Glu}_{1-5}}\)). The developed model was used to test hypotheses related to the enzymatic deglutamation of MTXGlu2–5 and potential loss of MTXGlu2–5 from RBCs.

Results

The final RBC pharmacokinetic model required the intracellular volumes of distribution for the parent and metabolites to be set to the value estimated for the parent drug MTX alone, and the rate constants describing the polyglutamation steps were fixed at literature values. Significant covariates included effect of body surface area-adjusted estimated glomerular filtration rate on renal plasma clearance and effect of allometrically scaled total body weight with a fixed exponent of 0.75 on non-renal plasma clearance of MTX. The only significant covariate with an effect on \({V}_{\text{Glu}_{1-5}}\) was mean corpuscular volume (MCV). The model supported single deglutamation steps and a single mechanism of MTX and MTXGlu2–5 loss from RBCs.

Conclusions

The developed model enabled acceptable description of the intracellular kinetics of MTX and MTXGlu2–5 in RBCs. In the future it can form the basis of a full pharmacokinetic–pharmacodynamic model to assess the time–RBC concentration–effect relationship of low-dose MTX treatment in RA.

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Acknowledgments

Drs J. O’Donnell and P. Chapman helped with data collection. Julia Korell received an Otago PhD Scholarship and Publishing Bursary. The Health Research Council of New Zealand gave funding for the clinical studies. No funding was received for this study. All authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Authors and Affiliations

  1. School of Pharmacy, University of Otago, PO Box 56, 9054, Dunedin, New Zealand

    Julia Korell & Stephen B. Duffull

  2. Department of Medicine, University of Otago, Christchurch, New Zealand

    Lisa K. Stamp, Murray L. Barclay, Jill Drake & Mei Zhang

  3. Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand

    Murray L. Barclay & Judith M. Dalrymple

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  1. Julia Korell
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  2. Lisa K. Stamp
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  3. Murray L. Barclay
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  4. Judith M. Dalrymple
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  5. Jill Drake
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  6. Mei Zhang
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  7. Stephen B. Duffull
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Correspondence to Julia Korell.

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Korell, J., Stamp, L.K., Barclay, M.L. et al. A Population Pharmacokinetic Model for Low-Dose Methotrexate and its Polyglutamated Metabolites in Red Blood Cells. Clin Pharmacokinet 52, 475–485 (2013). https://doi.org/10.1007/s40262-013-0052-y

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  • DOI: https://doi.org/10.1007/s40262-013-0052-y

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