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Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration

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Abstract

Purpose

Quantitative relationships between 9-β-d-arabinofuranosyl-2-fluoroadenine (F-ara-A) concentrations and lymphosuppression have not been reported, but would be useful for regimen design. A population pharmacokinetic/pharmacodynamic model was constructed in this study using data from 41 hematopoietic cell transplant (HCT) recipients conditioned with busulfan in combination with fludarabine (total dose 120 mg/m2, Protocol 1519) or with fludarabine (total dose 250 mg/m2) with rabbit antithymocyte globulin (rATG, Protocol 2041).

Methods

Individual pharmacokinetic parameters were fixed to post hoc Bayesian estimates, and circulating absolute lymphocyte counts (ALC) were obtained during the 3 weeks prior to graft infusion. A semi-physiological cell-kill model with three lymphocyte transit compartments was applied and aptly characterized the time course of suppression of circulating ALC by fludarabine administration. Drug- and system-specific parameters were estimated using a maximum likelihood expectation maximization algorithm, and the final model was qualified using an internal visual predictive check.

Results

The final model successfully characterized the time course and variability in ALC. Pharmacodynamic parameters exhibited considerable between subject variability (38.9–211 %). The HCT protocol was the only covariate associated with the pharmacodynamic parameters, specifically the lymphocyte kill rate, the transit rate between lymphocyte compartments, and the baseline ALC.

Conclusions

This model can be used to simulate the degree of lymphosuppression for design of future fludarabine-based conditioning regimens.

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Acknowledgments

Supported by grants from the National Institutes of Health: NHLBI (HL91744, HL36444), NCI (CA15704 (core), 18029, 78902), NIBIB (EB001975), and NIGMS (GM57980).

Author information

Author notes

  1. David H. Salinger

    Present address: Amgen Inc., Seattle, WA, USA

  2. Paolo Vicini

    Present address: Pfizer Global Research and Development, La Jolla, CA, USA

Authors and Affiliations

  1. Department of Pharmacy, School of Pharmacy, University of Washington, Box 357630, Seattle, WA, 98195, USA

    Jeannine S. McCune

  2. Department of Bioengineering, University of Washington, Seattle, WA, USA

    Paolo Vicini & David H. Salinger

  3. Department of Medicine, University of Washington, Seattle, WA, USA

    Paul V. O’Donnell & Brenda M. Sandmaier

  4. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Jeannine S. McCune, Paul V. O’Donnell & Brenda M. Sandmaier

  5. H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Claudio Anasetti

  6. University at Buffalo, SUNY , Buffalo, NY, USA

    Donald E. Mager

Authors
  1. Jeannine S. McCune
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  2. Paolo Vicini
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Correspondence to Jeannine S. McCune.

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McCune, J.S., Vicini, P., Salinger, D.H. et al. Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. Cancer Chemother Pharmacol 75, 67–75 (2015). https://doi.org/10.1007/s00280-014-2618-2

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  • DOI: https://doi.org/10.1007/s00280-014-2618-2

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