Busulfan in Infant to Adult Hematopoietic Cell Transplant Recipients: A Population Pharmacokinetic Model for Initial and Bayesian Dose Personalization

Abstract

Purpose Personalizing intravenous (IV) 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 IV 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 post-menstrual age was built from 12,380 busulfan concentration-time points obtained after IV 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 62kg normal fat mass (equivalent to 70kg 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 post-natal 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 to dosing recommended by the Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion This is the first population pharmacokinetic model developed to predict initial IV busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults.

Dexmedetomidine pharmacokinetics in the obese

“…The higher concentrations of dexmedetomidine observed in obese patients after receiving TBW-based schemes are explained by two factors: the lack of influence of fat mass on dexmedetomidine volume of distribution and impairment of dexmedetomidine clearance associated with fat mass. This impairment of clearance has not been reported for other drugs examined using either FFM or NFM as a size descriptor (gemcitabine [13], busulphan [20], ethanol [21], paracetamol [22], propofol [23]). The detection of an effect of fat mass on clearance may be due to inclusion of both non-obese and obese patients in our study.…”

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

“…Eleven publications describing 12 busulfan dosing guidelines were identified (Table 3) [6,7,[12][13][14][15][16][17][18][19][20]. One dosing guideline [19] was supplemented by an online dosage calculation tool (see http://holford.fmhs.auckland.ac.nz/ docs/busulfan-integrated-pk.pdf) [21].…”

“…One dosing guideline [19] was supplemented by an online dosage calculation tool (see http://holford.fmhs.auckland.ac.nz/ docs/busulfan-integrated-pk.pdf) [21]. Another was supplemented by an Excel-based dose calculator tool (Dr. J. R. LongBoyle, personal communication, March 16, 2015).…”

Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics

“…Of note, for continuous covariates, a VPC may be constructed using a covariate, such as body weight, age, or model predictions, as the independent variable. This does not lose power like data stratification methods and can provide useful confirmation of the appropriateness of a covariate model 9, 21…”