tobiasK2001
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7 years ago add Label: 2014, Academic Partner, children
Open tobiasK2001 opened 7 years ago
tobiasK2001
commented
7 years ago add Label: 2014, Academic Partner, children
https://www.ncbi.nlm.nih.gov/pubmed/25007236
Pediatr Hematol Oncol. 2014 Nov;31(8):731-42. doi: 10.3109/08880018.2014.927945. Epub 2014 Jul 9.
Diestelhorst C1, Boos J, McCune JS, Russell J, Kangarloo SB, Hempel G.
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.
KEYWORDS:
HSCT; bone marrow transplantation; busulfan; oncology; pharmacokinetics
PMID: 25007236 DOI: 10.3109/08880018.2014.927945