Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population

• Published in: Frontiers in pharmacology 2020-07, Vol.11, p.888
• Main Authors: Shukla, Praveen, Goswami, Srijib, Keizer, Ron J, Winger, Beth Apsel, Kharbanda, Sandhya, Dvorak, Christopher C, Long-Boyle, Janel
• Format: Article
• Language: English
• Subjects: busulfan; hematopoietic cell transplantation; pediatric; pharmacokinetics; Pharmacology; therapeutic drug monitoring
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.00888

Population pharmacokinetic (PK) studies demonstrate model-based dosing for busulfan that incorporates body size and age improve clinical target attainment as compared to weight-based regimens. Recently, for clinical dosing of busulfan and TDM, our institution transitioned to a cloud-based clinical decision support tool (www.insight-rx.com). The goal of this study was to assess the dose decision tool for the achievement of target exposure of busulfan in children undergoing hematopoietic cell transplantation (HCT). Patients (N = 188) were grouped into cohorts A, B, or C based on the method for initial dose calculation and estimation of AUC: Initial doses were based on the conventional dosing algorithm (as outlined in the manufacturers' package insert) and non-compartmental analysis (NCA) estimation using the trapezoidal rule for estimation of AUC following TDM. Initial doses for busulfan were estimated by a first-generation PK model and NCA estimation of AUC following TDM. Initial doses were calculated by an updated, second-generation PK model available in the dose decision tool with an estimation of AUC following TDM. The percent of individuals achieving the exposure target at the time of first PK collection was higher in subjects receiving initial doses provided by the model-informed precision dosing platform (cohort C, 75%) versus subjects receiving initial doses based on either of the two other approaches (conventional guidelines/cohort A, 25%; previous population PK model and NCA parameter estimation, cohort B, 50%). Similarly, the percent of subjects achieving the targeted cumulative busulfan exposure (cAUC) in cohort C was 100% vs. 66% and 88% for cohort A and B, respectively. For cAUC, the variability in the spread of target attainment (%CV) was low at 4.1% for cohort C as compared to cohort A (14.8%) and cohort B (17.1%). Achievement of goal exposure early on in treatment was improved with the updated model for busulfan and the Bayesian platform. Model-informed dosing and TDM utilizing a Bayesian-based platform provides a significant advantage over conventional guidelines for the achievement of goal cAUC exposure.