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Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration.

McCune, Jeannine S; Vicini, Paolo; Salinger, David H; O'Donnell, Paul V; Sandmaier, Brenda M; Anasetti, Claudio; Mager, Donald E.
Cancer Chemother Pharmacol; 75(1): 67-75, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25374408

PURPOSE:

Quantitative relationships between 9-ß-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.
Selo DaSilva