6ae28c4a7cd2a698db469e90e72dd870 pharmaceutics-17-01592.pdf 5a8bd223e4cec8317bd049950b9cb2f40ec9c51e pharmaceutics-17-01592.pdf 387608347e12b057ce9cb24f037d00828cef3f180efbc93dcfcaa3f866f6bc3d pharmaceutics-17-01592.pdf Title: Towards Personalized Lymphodepletion: A Population Pharmacokinetic Fludarabine Model in Patients Receiving CAR T-Cell Therapy Subject: Background/Objectives: Optimal fludarabine dosing in the conditioning regimen based on population pharmacokinetic analysis (popPK) can predict outcomes in patients receiving hematopoietic stem cell transplantation. To date, there is no popPK tailored for patients receiving fludarabine as part of the lymphodepleting regimen before chimeric antigen receptor (CAR) T-cell infusion. The objective of this study was to develop a PopPK model of fludarabine in patients receiving CAR T-cell therapy. Methods: A prospective study was conducted at 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, 7 and 24 h post-fludarabine doses, and 30 min prior to CART-cell infusion. Fludarabine levels were analyzed through an ultra-performance liquid chromatography tandem mass spectrometry assay based on liquid–liquid extraction. Population pharmacokinetic analysis modeling was performed using nonlinear mixed-effects models (NONMEM). Results: Fifty-six patients (59% male) with a median age of 59 years (range 23–82) received CAR T-cell therapy (38 [68%] axicabtagene ciloleucel, 18 [32%] tisagenlecleucel) for relapsed/refractory large B-cell lymphoma. A total of 348 samples were collected for model development. A three-compartment model with first-order elimination best described the data. Body size, as represented by weight (WGT) with allometric scaling, was a significant predictor of all pharmacokinetic parameters (p < 0.05). Estimated glomerular filtration rate (eGFR) and the CAR T-cell construct type also showed statistical significance for fludarabine clearance (CL) (p < 0.05). Clearance was differentiated into non-renal and renal components. Estimates of V1, V2 and V3 volumes (the apparent volume of distribution of the central, shallow and deep compartments) were 41.2, 14.5 and 10.8 L, respectively. Conclusions: WGT, eGFR and type of CAR-T were predictors of fludarabine pharmacokinetics. This model offers a step toward precision-guided lymphodepletion and might support individualized dosing to optimize efficacy and minimize toxicity. Keywords: pharmacokinetics; fludarabine; population pharmacokinetic model; non-Hodgkin lymphoma Author: Javier Varela-González-Aller, Mario Andrés Sánchez-Salinas, Iñaki Troconiz, Gloria Iacoboni, Carla Alonso-Martínez, Maria-Josep Carreras-Soler, Cecilia Carpio, Anna Farriols-Danes, María Guerra-González, Alfredo Rivas-Delgado, Lucas Rivera Sanchez, Samantha Feijoo, Carolina Valdivia, Pere Barba and Marta Miarons Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Thu Dec 11 09:45:24 2025 CET ModDate: Thu Dec 11 09:53:45 2025 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2367772 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- LZOLHU+URWPalladioL-Bold Type 1 Custom yes yes yes 125 0 XEEXDI+URWPalladioL-Roma Type 1 Custom yes yes yes 126 0 SSXPJJ+VnURWPalladioL Type 1 Custom yes yes yes 127 0 ASZBXY+URWPalladioL-Ital Type 1 Custom yes yes yes 128 0 WCBROF+EURM10 Type 1 Builtin yes yes yes 166 0 WVRPRN+CMSY10 Type 1 Builtin yes yes yes 191 0 URYLRZ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 229 0 LJJDGL+PalatinoLinotype TrueType WinAnsi yes yes no 245 0 LJJDGJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 246 0 LJJMEL+CambriaMath TrueType WinAnsi yes yes no 321 0 LJJDGL+PalatinoLinotype TrueType WinAnsi yes yes no 322 0 LJJDGJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 323 0 SOSTRQ+CMR10 Type 1 Builtin yes yes yes 350 0 HWWYCD+PazoMath-Italic Type 1 Builtin yes yes yes 351 0 WQITEV+CMEX10 Type 1 Builtin yes yes yes 352 0 LJJDGL+PalatinoLinotype TrueType WinAnsi yes yes no 345 0 LJJDGJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 346 0 LJJDGL+PalatinoLinotype TrueType WinAnsi yes yes no 370 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-03-07 04:41:47 CET RepresentationInformation: pharmaceutics-17-01592.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-03-06 14:39:30 CET Size: 2367772 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 510 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Materials and Methods Children: Item: Title: Study Design Children: Item: Title: Fludarabine Dosing Item: Title: Subjects Item: Title: Blood Sampling Collection Item: Title: Analytical Determination Item: Title: Population Pharmacokinetics Analysis Children: Item: Title: Base Population Model Item: Title: Covariate Selection Item: Title: Model Evaluation Item: Title: Results Children: Item: Title: Patient Characteristics Item: Title: Samples Item: Title: Population PK Modeling Item: Title: Model Evaluation Item: Title: Discussion Item: Title: Conclusions Item: Title: References Info: Title: Towards Personalized Lymphodepletion: A Population Pharmacokinetic Fludarabine Model in Patients Receiving CAR T-Cell Therapy Author: Javier Varela-González-Aller, Mario Andrés Sánchez-Salinas, Iñaki Troconiz, Gloria Iacoboni, Carla Alonso-Martínez, Maria-Josep Carreras-Soler, Cecilia Carpio, Anna Farriols-Danes, María Guerra-González, Alfredo Rivas-Delgado, Lucas Rivera Sanchez, Samantha Feijoo, Carolina Valdivia, Pere Barba and Marta Miarons Subject: Background/Objectives: Optimal fludarabine dosing in the conditioning regimen based on population pharmacokinetic analysis (popPK) can predict outcomes in patients receiving hematopoietic stem cell transplantation. To date, there is no popPK tailored for patients receiving fludarabine as part of the lymphodepleting regimen before chimeric antigen receptor (CAR) T-cell infusion. The objective of this study was to develop a PopPK model of fludarabine in patients receiving CAR T-cell therapy. Methods: A prospective study was conducted at 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, 7 and 24 h post-fludarabine doses, and 30 min prior to CART-cell infusion. Fludarabine levels were analyzed through an ultra-performance liquid chromatography tandem mass spectrometry assay based on liquid–liquid extraction. Population pharmacokinetic analysis modeling was performed using nonlinear mixed-effects models (NONMEM). Results: Fifty-six patients (59% male) with a median age of 59 years (range 23–82) received CAR T-cell therapy (38 [68%] axicabtagene ciloleucel, 18 [32%] tisagenlecleucel) for relapsed/refractory large B-cell lymphoma. A total of 348 samples were collected for model development. A three-compartment model with first-order elimination best described the data. Body size, as represented by weight (WGT) with allometric scaling, was a significant predictor of all pharmacokinetic parameters (p < 0.05). Estimated glomerular filtration rate (eGFR) and the CAR T-cell construct type also showed statistical significance for fludarabine clearance (CL) (p < 0.05). Clearance was differentiated into non-renal and renal components. Estimates of V1, V2 and V3 volumes (the apparent volume of distribution of the central, shallow and deep compartments) were 41.2, 14.5 and 10.8 L, respectively. Conclusions: WGT, eGFR and type of CAR-T were predictors of fludarabine pharmacokinetics. This model offers a step toward precision-guided lymphodepletion and might support individualized dosing to optimize efficacy and minimize toxicity. 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