Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration

Cancer Chemother Pharmacol. 2015 Jan;75(1):67-75. doi: 10.1007/s00280-014-2618-2. Epub 2014 Nov 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / blood
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Antimetabolites, Antineoplastic / therapeutic use
  • Child
  • Cohort Studies
  • Half-Life
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Humans
  • Immunosuppression Therapy / adverse effects*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics*
  • Immunosuppressive Agents / therapeutic use
  • Leukemia, Myeloid / blood
  • Leukemia, Myeloid / immunology
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / therapy
  • Lymphocyte Count
  • Lymphopoiesis / drug effects*
  • Middle Aged
  • Models, Biological*
  • Myeloproliferative Disorders / blood
  • Myeloproliferative Disorders / immunology
  • Myeloproliferative Disorders / metabolism
  • Myeloproliferative Disorders / therapy
  • Reproducibility of Results
  • Retrospective Studies
  • Transplantation Conditioning / adverse effects*
  • Vidarabine Phosphate / adverse effects
  • Vidarabine Phosphate / analogs & derivatives*
  • Vidarabine Phosphate / blood
  • Vidarabine Phosphate / pharmacokinetics
  • Vidarabine Phosphate / therapeutic use
  • Young Adult

Substances

  • Antimetabolites, Antineoplastic
  • Immunosuppressive Agents
  • Vidarabine Phosphate
  • fludarabine phosphate