The impact of age and renal function on the pharmacokinetics and protein binding characteristics of fludarabine in paediatric and adult patients undergoing allogeneic haematopoietic stem cell transplantation conditioning.

Abstract

To evaluate the population pharmacokinetics of unbound F-Ara-A (the circulating metabolite of fludarabine) in 211 patients (age range, 0.1-63.4years) undergoing allogeneic haematopoietic stem cell transplantation conditioning. Total (n = 2480) and unbound (n = 1403) F-Ara-A concentrations were measured in blood samples collected at timed intervals after fludarabine doses ranging from 10 to 50mg/m2 and infused over 0.42-1.5h. A three-compartment population pharmacokinetic model was developed based on unbound plasma concentrations and used to estimate F-Ara-A unbound pharmacokinetic parameters and fraction unbound (fu). A number of covariates, including glomerular filtration rate (GFR) and post-menstrual age (PMA), were evaluated for inclusion in the model. The base population mean estimates ± relative standard error (%RSE) for unbound clearance from the central compartment (CLu) and inter-compartmental clearances (Q2u, Q3u) were 3.42 ± 3%, 6.54 ± 24% and 1.47 ± 16% L/h/70kg, respectively. The population mean estimates (%RSE) for the unbound volume of distribution into the central (V1u) and peripheral compartments (V2u, V3u) were 9.65 ± 8%, 8.17 ± 9% and 16.4 ± 10% L/70kg, respectively, and that for fu was 0.877 ± 1%. Covariate model development involved differentiating F-Ara-A CLu into non-renal (1.81 ± 9% L/h/70kg) and renal components (1.02 ± 9%*GFR L/h/70kg). A sigmoidal maturation factor was applied to renal CLu, with population mean estimates for the Hill exponent and PMA at 50% mature of 2.97 ± 4% and 69.1 ± 8%weeks, respectively. Patient age and GFR are predictors of unbound F-Ara-A CLu. This has the potential to impact dose requirements. Dose individualisation by target concentration intervention will be facilitated by this model once it is externally validated.