Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration

• Published in: Cancer chemotherapy and pharmacology Vol. 75; no. 1; pp. 67 - 75
• Main Authors: McCune, Jeannine S., Vicini, Paolo, Salinger, David H., O’Donnell, Paul V., Sandmaier, Brenda M., Anasetti, Claudio, Mager, Donald E.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2015; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - therapeutic use; Cancer Research; Child; Cohort Studies; Half-Life; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Immunosuppression - 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; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Myeloproliferative Disorders - blood; Myeloproliferative Disorders - immunology; Myeloproliferative Disorders - metabolism; Myeloproliferative Disorders - therapy; Oncology; Original Article; Pharmacology/Toxicology; 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; Hematopoietic cell transplantation; Fludarabine; Population pharmacodynamics; Adoptive immunotherapy; Lymphocyte; Lymphosuppression; Nucleoside analogs
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2618-2

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/m 2 ) 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.