4CPS-132 Population pharmacokinetic model of fludarabine in patients undergoing chimeric antigen receptor t cells therapy

<h3>Background and Importance</h3> Optimal fludarabine dosing based on population pharmacokinetic analysis (popPK) can predict outcomes in patients undergoing myeloablative conditioning prior to haematopoietic stem cell transplantation.^{1 2} To date, there is no popPK tailored for patients receiving fludarabine as part of lymphodepleting regimen before chimeric antigen receptor T (CAR-T). <h3>Aim and Objectives</h3> To develop a especific PopPK model of fludarabine in patients undergoing CAR-T-cell therapy. <h3>Material and Methods</h3> A prospective study was conducted at the Haematology Department of a tertiary hospital, from January 2021 to July 2022. Demographic, clinical, and analytical variables were collected. Blood samples were obtained on days 1 and 3 of the lymphodepleting regimen at 1.5, 2, and 24 hours post-fludarabine doses (3 total doses) and 30 minutes prior to CAR-T infusion. Fludarabine levels were analysed through an ultra-performance liquid chromatography tandem mass spectrometry assay based on liquid-liquid extraction. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). <h3>Results</h3> Fifty-six patients (59% male) with a mean age of 59 years (range: 23–82) received CAR-T-cell therapy (38 [67.8%] axicabtagene-ciloleucel (axi-cel); 18 [32.2%] tisagenlecleucel (tisa-cel)). A total of 353 samples were collected for model development. A three-compartment model with first-order kinetics best described the data. Body size, as represented by actual body weight (ABW) with allometric scaling, was a significant predictor of all pharmacokinetic parameters. CAR-T construct and estimated glomerular filtration rate (eGFR) also showed statistical significance for clearance (CL). CL was differentiated into a non-renal (4.4 ± 1.2% L/h/70 kg and 3.9 ± 0.95% L/h/70 kg for axi-cel and tisa-cel, respectively) and renal (1.7±1.0%x(eGFR)x(ABW/70)^0.75 L/h/70 kg) component. Estimates of V1, V2 and V3 (central, peripheral and second peripheral distribution volumes) were 41.2 ± 9% L/70 kg, 14.5 ± 14% L/70 kg, and 10.8 ± 3% L/70 kg, respectively. Intercompartmental clearances between V1 and V2, and V1 and V3, were 4.8 ± 5.3% and 3.6 ±0.04% L/h/70 kg. <h3>Conclusion and Relevance</h3> ABW, eGFR and type of CAR-T are important predictors of fludarabine pharmacokinetics. Further investigation is needed to elucidate optimal fludarabine dosing through popPK model and its correlation with outcomes in CAR-T-cell therapy. <h3>References and/or Acknowledgements</h3> doi:10.1007/s40262-018-0715-9 doi:10.1182/bloodadvances.2018029421 <h3>Conflict of Interest</h3> No conflict of interest