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


METHODS
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%).


CONCLUSIONS
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.
Authors' Affiliations: University of Washington Schools of Pharmacy and Medicine; Fred Hutchinson Cancer Research Center; Seattle Children's Hospital, Seattle, Washington; Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Children's Mercy Hospitals and Clinics, Kansas City, Missouri; and Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Jeannine S
JS
McCune
Meagan J
MJ
Bemer
Jeffrey S
JS
Barrett
K
K
Scott Baker
Alan S
AS
Gamis
Nicholas H G
NH
Holford
D000293:Adolescent; D000328:Adult; D001499:Bayes Theorem; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D057285:Precision Medicine; D019172:Transplantation Conditioning / Q000379:methods*; D055815:Young Adult
D019653:Myeloablative Agonists; D002066:Busulfan