Hyewon Chung (1), Su-jin Rhee (1), Kyung Taek Hong (2), Hyoung Jin Kang (2), In-Jin Jang (1), Kyung-Sang Yu (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, (2) Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
Objectives: Fludarabine, a prodrug that is dephosphorylated to F-ara-A [1], is used as a component of conditioning regimens of hematopoietic stem cell transplantation (HSCT). However, the pharmacokinetic (PK) data of F-ara-A in pediatric patients is limited. The objective of this study was to develop a population PK model of F-ara-A after fludarabine administration in pediatric patients.
Methods: A total of 802 samples obtained from 43 pediatric patients were included for population PK analysis. Among them, 40 patients received fludarabine 40mg/m2 as a 30 minute infusion once daily for 6 days. The analysis was performed using non-linear mixed-effects modelling as implemented in NONMEM version 7.3. Covariates including body surface area (BSA), weight, age, serum creatinine, and sex were evaluated and the final model was selected based on decrease in objective function, diagnostic plots, and visual predictive check.
Results: A two-compartmental model with proportional residual error adequately described the PK of F-ara-A. BSA was a significant covariate for clearance (CL), central volume of distribution (V2), and peripheral volume of distribution (V2) using a power function. The typical population estimates of CL, V1, and V2 for a subject with BSA of 1.254 m2 were 10.4 L/h, 36.8 L, and 43.2 L, respectively. The inter-individual variability were described for CL (30.7%), V1 (23.9%), V2 (25.6%), and inter-compartmental clearance (35.7%).
Conclusions: Population PK parameters for F-ara-A were successfully estimated in paediatric patients. This model can be used to guide fludarabine therapy, and to evaluate relationships between PK and clinical outcome.
References:
[1] Gandhi, V, Plunkett, W. Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet (2002) 41(2):93-103.
Reference: PAGE 25 () Abstr 5840 [www.page-meeting.org/?abstract=5840]
Poster: Drug/Disease modeling - Paediatrics