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.

Praveen Shukla,Christopher C Dvorak,Janel Long-Boyle,Beth Apsel Winger,Srijib Goswami,Ron J Keizer,Sandhya Kharbanda

doi:10.3389/fphar.2020.00888

Praveen Shukla, Christopher C Dvorak + Show 5 more

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https://doi.org/10.3389/fphar.2020.00888

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Abstract

IntroductionPopulation 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 and MethodsPatients (N = 188) were grouped into cohorts A, B, or C based on the method for initial dose calculation and estimation of AUC: Cohort A: 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. Cohort B: Initial doses for busulfan were estimated by a first-generation PK model and NCA estimation of AUC following TDM. Cohort C: Initial doses were calculated by an updated, second-generation PK model available in the dose decision tool with an estimation of AUC following TDM.ResultsThe 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%).ConclusionAchievement 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.

Highlights

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
Busulfan is a bifunctional alkylating agent commonly used in conditioning regimens prior to hematopoietic cell transplantation (HCT) for the treatment of a variety of childhood diseases, including both malignant and nonmalignant disorders
Due to the erratic population pharmacokinetic (PK) profile in children (Vassal et al, 1989; Slattery et al, 1995; Bolinger et al, 2001; Mccune et al, 2002; Nguyen et al, 2004) and well-described exposure-response relationships, the therapeutic drug monitoring (TDM) for busulfan is performed as a part of the standard clinical care in children undergoing HCT (Vassal et al, 1989; Slattery et al, 1995; Bolinger et al, 2001; Mccune et al, 2002; Nguyen et al, 2004; Palmer et al, 2016)

Summary

Introduction

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. 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). Wide-spread clinical practice for busulfan dosing has followed the FDA-approved drug label, with an initial busulfan dose estimation based on actual body weight (Anonymous, 2015). This “conventional dosing” nomogram recommends an initial dose of 1.1 mg/kg for patients weighing ≤12 kg and initiating therapy at 0.8 mg/kg/dose for patients weighing >12 kg, regardless of age. There are several limitations to these conventional-dose nomograms when applied to clinical use in children, in the very young and this often leads to suboptimal busulfan exposure, graft failure, and significant drug-related morbidity and mortality

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