Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration.
OBJECTIVE
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.
Department of Pharmacy, School of Pharmacy, University of Washington, Box 357630, Seattle, WA, 98195, USA, jmccune@u.washington.edu.
Jeannine S
JS
McCune
Paolo
P
Vicini
David H
DH
Salinger
Paul V
PV
O'Donnell
Brenda M
BM
Sandmaier
Claudio
C
Anasetti
Donald E
DE
Mager
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D006207:Half-Life; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018655:Lymphocyte Count; D038041:Lymphopoiesis / Q000187:drug effects*; D008875:Middle Aged; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D015203:Reproducibility of Results; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000009:adverse effects*; D001084:Vidarabine Phosphate / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate