Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration

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 three 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.

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

“…[30,31] The design of new fludarabine-based conditioning regimens may benefit from the use of a population pharmacodynamic model that characterizes the time course and variability of absolute lymphocyte count suppression – which affects a mixed population of T cells, B cells, and natural killer cells – by plasma F-ara-A. [32]…”

Rapid Advances in Immunotherapy to Treat Cancer

“…The final step is the patient receiving a lymphodepleting chemotherapy infusion followed by infusion of the CAR T cells. These empirically chosen lymphodepleting chemotherapy regimens often include cyclophosphamide and fludarabine; there is a paucity of pharmacokinetic/dynamic (PK/PD) models of their lymphodepletion . After administration, the engineered CAR T cells should further multiply in the patient's body and, with guidance from their engineered receptor, recognize and kill cancer cells that express the antigen on their surfaces.…”

“…In this themed issue, Annesley et al describe the development of CAR T cells with CD19 specificity and the remaining challenges, such as production time, early loss of CAR T cells, relapse due to loss of the target antigen, and prevention of severe cytokine release syndrome (CRS) and neurotoxicity. The early loss of CAR T cells may be minimized by more aggressive lymphodepletion of the conditioning regimen, which may be achieved by population PK/PD modeling of lymphodepletion 6 and/or population PK-guided dosing of cyclophosphamide. 7 Overcoming the remaining challenges to CAR T-cell therapy is critical, since ALL is the most common cancer afflicting children, with long-term survival rates approaching 90%.…”

Individualized conditioning regimes in cord blood transplantation: Towards improved and predictable safety and efficacy

“…may play a role in T-cell IR. [97,98] The project is aimed at describing the population PK and PD of Flu in order to derive individualized dosing nomograms.…”

“…To our best knowledge, these are the only drugs used in the conditioning regimen in allogeneic HCT for which individualized dosing regimens are available. However, efforts have been made to characterize the PK and PD of other drugs used including Flu, [98,110] treosulfan [68] and Cy, [111] which however did not yet result in practical guidelines or dosing recommendations.…”