Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation
Jordan T. Brooks,
Belen P. Solans,
Ying Lu,
Sandhya Kharbanda,
Christopher C. Dvorak,
Nahal Lalefar,
Susie Long,
Ashish O. Gupta,
Biljana Horn,
Jatinder K. Lamba,
Liusheng Huang,
Beth Apsel-Winger,
Ron J. Keizer,
Rada Savic,
Janel Long-Boyle
Affiliations
Jordan T. Brooks
Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
Belen P. Solans
Department of Bioengineering and Therapeutics, University of California San Francisco, San Francisco, CA 94143, USA
Ying Lu
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA
Sandhya Kharbanda
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA
Christopher C. Dvorak
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA
Nahal Lalefar
Benioff Children’s Hospital of Oakland, University of California San Francisco, Oakland, CA 94609, USA
Susie Long
Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN 55454, USA
Ashish O. Gupta
Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN 55454, USA
Biljana Horn
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Jatinder K. Lamba
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Liusheng Huang
Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
Beth Apsel-Winger
Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
Ron J. Keizer
Insight RX, San Francisco, CA 94104, USA
Rada Savic
Department of Bioengineering and Therapeutics, University of California San Francisco, San Francisco, CA 94143, USA
Janel Long-Boyle
Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.
