Population pharmacokinetic (popPK)-guided dosing of fludarabine in conditioning regimens has been shown to influence clinical outcomes in hematopoietic stem cell transplantation. However, no popPK model has yet been specifically developed for patients receiving fludarabine as part of lymphodepletion before chimeric antigen receptor (CAR) T-cell therapy. The present study aimed to establish a population pharmacokinetic model of fludarabine in this setting. This prospective study was carried out at a tertiary care hospital between January 2021 and July 2022. Demographic, clinical, and laboratory data were collected for all participants. Blood samples were obtained on days 1 and 3 of the lymphodepleting regimen at multiple post-dose time points (1.5, 2, 7, and 24 hours) and immediately before CAR T-cell infusion. Plasma concentrations of fludarabine were quantified using an ultra-performance liquid chromatography–tandem mass spectrometry method following liquid–liquid extraction. Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling (NONMEM). A total of 56 patients (59% male) with a median age of 59 years (range 23–82) were included, all treated with CAR T-cell therapy for relapsed or refractory large B-cell lymphoma. Among them, 68% received axicabtagene ciloleucel and 32% received tisagenlecleucel. In total, 348 concentration samples were available for model development. The data were best described by a three-compartment model with first-order elimination. Body weight, when scaled allometrically, was identified as a significant determinant of all pharmacokinetic parameters (P < 0.05). In addition, estimated glomerular filtration rate (eGFR) and the type of CAR T-cell product were significantly associated with drug clearance (P < 0.05), which was modeled as a combination of renal and non-renal pathways. The estimated volumes of distribution for the central, shallow peripheral, and deep peripheral compartments (V1, V2, V3) were 41.2 L, 14.5 L, and 10.8 L, respectively. Overall, body weight, renal function, and CAR T-cell product type were identified as key factors influencing fludarabine pharmacokinetics. These findings support the potential use of this model to guide individualized lymphodepletion strategies, aiming to improve efficacy while reducing treatment-related toxicity.
