Purpose: We have developed a pharmacokinetic model of intravenous (IV) busulfan that is applicable from neonates to adults that accounts for differences in size, body composition and age.
Experimental design: Routinely collected busulfan concentration profiles were obtained at a national center for measuring busulfan concentrations. Dosing and demographic data was matched with 12,380 concentrations in 1610 patients. Most (92%) of the patients were under the age of 20.
Results: IV busulfan pharmacokinetics were characterized with a two-compartment model with first-order elimination and first order elimination. PK parameters were scaled using theory based allometry based on normal fat mass. Female sex was associated with a slightly (4%) higher volume of distribution. Malignant compared to non-malignant disease was not associated with different pharmacokinetic parameters. The median IV busulfan clearance and volume of the central compartment were 12.5 L/hr and 21.8 L, respectively, for a 70 kg (normal fat mass) male. Clearance reached half of the adult value at 45.6 weeks post-menopausal age with Hill coefficient of 2.3 for a sigmoidal Emax maturation function. At 2.5 years postnatal age, busulfan clearance is predicted to be 95% of the adult clearance. On the basis of our model and other published models, we predicted the initial busulfan dose and compared it to the individual dose predicted from the empirical Bayes estimate of clearance in order to achieve the product label recommended target AUC0-6h of 1125 uM*min.
Conclusion: We recommend a normal fat mass-based dosing regimen for personalizing IV busulfan doses from neonates to adults to reduce variability in busulfan AUC and to improve clinical outcomes of busulfan-based conditioning regimens.