title: Predictive performance of a physiologically based pharmacokinetic model of busulfan in children.
abstract: A physiologically based pharmacokinetic (PBPK) model of the DNA-alkylating agent busulfan was slightly modified and scaled from adults to children in order to predict the systemic busulfan drug exposure in children. Capitalizing on the recent major software release of PK-Sim®, we refined our PBPK model by implementing glutathione S transferase (GST) in 11 organs using the software integrated enzyme expression database. In addition, two irreversible binding processes (i.e., DNA and plasma protein binding) were applied by using Koff and KD values. The model was scaled from adults to children. Simulations were computed and compared to concentration-time data after intravenous (i.v.) busulfan administration to 36 children. Based on the results, an age-dependent enzyme activity and maturation ratio was tailored and evaluated with an external dataset consisting of 23 children. Initial adult to children scaling indicated lower clearance values for children in comparison to adults. Subsequent age-dependent maturation ratio resulted in three different age groups: Activity of busulfan-glutathione conjugate formation was 80%, 61%, and 89% in comparison to adults for children with an age of up to 2 years, > 2-6 years, and > 6-18 years, respectively. Patients of the evaluation dataset were simulated with a mean percentage error (MPE) for all patients of 3.9% with 3/23 children demonstrating a MPE of > ±30%. The PBPK model parameterization sufficiently described the observed concentration-time data of the validation dataset while showing an adequate predictive performance. This PBPK model could be helpful to determine the first dose of busulfan in children.
authors.affiliation: 1Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Diestelhorst
authors.forename: Joachim
authors.initials: J
authors.lastname: Boos
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: James
authors.initials: J
authors.lastname: Russell
authors.forename: S Bill
authors.initials: SB
authors.lastname: Kangarloo
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
mesh_terms: D000293:Adolescent; D000328:Adult; D000477:Alkylating Agents / Q000097:blood / Q000493:pharmacokinetics*; D002066:Busulfan / Q000097:blood / Q000493:pharmacokinetics*; D002170:Canada; D002648:Child; D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008954:Models, Biological; D012984:Software; D019172:Transplantation Conditioning
chemical_list: D000477:Alkylating Agents; D002066:Busulfan
keywords: HSCT; bone marrow transplantation; busulfan; oncology; pharmacokinetics