Journal
CLINICAL CANCER RESEARCH
Volume 20, Issue 3, Pages 754-763Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-1960
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Funding
- Otsuka Pharmaceutical of North America
- UW DMTPR
- University of Auckland
- Children's Oncology Group Chair's grant [NIH U10 CA98543, SDC U10 CA98413, U10 HD037255, RC1 LM010367-01]
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Purpose: Personalizing intravenous busulfan doses to a target plasma concentration at steady state (C-ss) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1-66 years) that accounts for differences in age and body size. Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target C-ss with this model were compared with pediatric-only models. Results: A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size-specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target C-ss of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U. S. Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target C-ss over a wide age spectrum, ranging from infants to adults. (C) 2013 AACR.
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