Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use

Abstract

Background: Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation.

Patients and methods: Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model.

Results: Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02).

Conclusions: When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

Conflict of interest statement

CONFLICT OF INTEREST

The authors have no conflicts of interest to disclose.

Figures

Figure 1

Panel A- Comparison between individual busulfan CL estimates with single dose (test dose or first dose) and steady-state doses (n=58); Panel B- Change in busulfan CLin for the typical patient with plasma concentrations1; Panel C- Plot of inter-individual variability of CLin versus age.2 1 Dark line represents the change in busulfan CL of a typical patient of 22 kg and 7 years of age with busulfan concentrations. Dashed lines represent the range of the observed busulfan concentrations in our study (250–2000 ng/mL); dotted lines are the target busulfan concentrations (600–900 ng/mL). 2 Black dots represent the individual values of ETA1 (random effect on CLin), the grey line represents the smooth line.

Figure 1

Panel A- Comparison between individual busulfan CL estimates with single dose (test dose or first dose) and steady-state doses (n=58); Panel B- Change in busulfan CLin for the typical patient with plasma concentrations1; Panel C- Plot of inter-individual variability of CLin versus age.2 1 Dark line represents the change in busulfan CL of a typical patient of 22 kg and 7 years of age with busulfan concentrations. Dashed lines represent the range of the observed busulfan concentrations in our study (250–2000 ng/mL); dotted lines are the target busulfan concentrations (600–900 ng/mL). 2 Black dots represent the individual values of ETA1 (random effect on CLin), the grey line represents the smooth line.

Figure 1

Panel A- Comparison between individual busulfan CL estimates with single dose (test dose or first dose) and steady-state doses (n=58); Panel B- Change in busulfan CLin for the typical patient with plasma concentrations1; Panel C- Plot of inter-individual variability of CLin versus age.2 1 Dark line represents the change in busulfan CL of a typical patient of 22 kg and 7 years of age with busulfan concentrations. Dashed lines represent the range of the observed busulfan concentrations in our study (250–2000 ng/mL); dotted lines are the target busulfan concentrations (600–900 ng/mL). 2 Black dots represent the individual values of ETA1 (random effect on CLin), the grey line represents the smooth line.

Figure 2

Panel A- Model predicted and measured (observed) plasma busulfan plasma concentrations obtained using the population model in the validation cohort plotted versus time. 1 Panel B- Prediction-corrected visual predictive check of the concentration-time profile predicted by the original busulfan PK model versus the concentrations observed in the validation dataset. 2 1 Panel A- Light grey circles represent the observed concentrations in the validation dataset. The filled dark squares represent the simulated concentration by the final population PK model. 2 Panel B- The solid grey lines represent the 2.5th percentile, median and 95th percentile of the prediction corrected observed plasma concentrations. The semitransparent dark grey field represents a simulation-based 95% confidence interval for the median and the semitransparent light grey fields show the 95% confidence intervals of the simulated data.

Figure 2

Panel A- Model predicted and measured (observed) plasma busulfan plasma concentrations obtained using the population model in the validation cohort plotted versus time. 1 Panel B- Prediction-corrected visual predictive check of the concentration-time profile predicted by the original busulfan PK model versus the concentrations observed in the validation dataset. 2 1 Panel A- Light grey circles represent the observed concentrations in the validation dataset. The filled dark squares represent the simulated concentration by the final population PK model. 2 Panel B- The solid grey lines represent the 2.5th percentile, median and 95th percentile of the prediction corrected observed plasma concentrations. The semitransparent dark grey field represents a simulation-based 95% confidence interval for the median and the semitransparent light grey fields show the 95% confidence intervals of the simulated data.

Figure 3

A computer screen shot of the Excel-based tool used to determine initial doses of busulfan based on the population PK model dosing algorithm.