Implementation and Cross-Validation of a Pharmacokinetic Model for Precision Dosing of Busulfan in Hematopoietic Stem Cell Transplanted Children

• Main Authors: Sylvain Goutelle (Author), Yann Thoma (Author), Roxane Buffet (Author), Michael Philippe (Author), Thierry Buclin (Author), Monia Guidi (Author), Chantal Csajka (Author)
• Format: Book
• Published: MDPI AG, 2022-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics14102107; 1999-4923
• Keywords: busulfan; pediatrics; hematopoietic stem cell transplantation; oncology; population pharmacokinetics; therapeutic drug monitoring; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 14, Iss 10, p 2107 (2022)

Busulfan, a drug used in conditioning prior to hematopoietic stem cell transplantation (HSCT) in children, has a narrow therapeutic margin. The model-informed precision dosing (MIPD) of busulfan is desirable, but there is a lack of validated tools. The objective of this study was to implement and cross-validate a population pharmacokinetic (PK) model in the Tucuxi software for busulfan MIPD in HSCT children. A search of the literature was performed to identify candidate population PK models. The goodness of fit of three selected models was assessed in a dataset of 178 children by computing the mean error (ME) and root-mean-squared error of prediction (RMSE). The best model was implemented in Tucuxi. The individual predicted concentrations, the area under the concentration-time curve (AUC), and dosage requirements were compared between the Tucuxi model and a reference model available in the BestDose software in a subset of 61 children. The model from Paci et al. best fitted the data in the full dataset. In a subset of 61 patients, the predictive performance of Tucuxi and BestDose models was comparable with ME values of 6.4% and −2.5% and RMSE values of 11.4% and 13.6%, respectively. The agreement between the estimated AUC and the predicted dose was good, with 6.6% and 4.9% of the values being out of the 95% limits of agreement, respectively. To conclude, a PK model for busulfan MIPD was cross-validated and is now available in the Tucuxi software.