Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and Bayesian dose personalization

Abstract

Purpose: Personalizing intravenous busulfan doses to a target plasma concentration at steady state (Css) 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 Css 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 Css 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 Css over a wide age spectrum, ranging from infants to adults.

Figure 1

Visual predictive checks (VPCs) by total body weight for overall cohort (A), by post-natal age (PNA) for the overall cohort (B) and by PNA for children (C). Dashed lines represent the 5^th and 95^th percentiles of the observed data. Solid lines represent the 5^th and 95^th percentiles of simulated data. Open circles and crosses represent 50^th percentile of observed and simulated data. Please note that most adults received daily IV busulfan as per the clinical protocol at the time.

Figure 2

Maturation of size standardized IV busulfan clearance, as L/h/62 kg normal fat mass (NFM). Symbols are empirical Bayes estimates scaled to 62kg NFM. The solid line is the predicted maturation function for IV busulfan clearance.