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01-01-2015 | Original Article

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration

Authors: Jeannine S. McCune, Paolo Vicini, David H. Salinger, Paul V. O’Donnell, Brenda M. Sandmaier, Claudio Anasetti, Donald E. Mager

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2015

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/m^2, 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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Title: Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration
Authors: Jeannine S. McCune
Paolo Vicini
David H. Salinger
Paul V. O’Donnell
Brenda M. Sandmaier
Claudio Anasetti
Donald E. Mager
Publication date: 01-01-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2618-2

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Purpose

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Results

Conclusions

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