Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software

Abstract

Background: Busulfan dose adjustment is routinely guided by plasma concentration monitoring using 4-9 blood samples per dose adjustment, but a pharmacometric Bayesian approach could reduce this sample burden.

Methods: The authors developed a nonparametric population model with Pmetrics. They used it to simulate optimal initial busulfan dosages, and in a blinded manner, they compared dosage adjustments using the model in the BestDose software to dosage adjustments calculated by noncompartmental estimation of area under the time-concentration curve at a national reference laboratory in a cohort of patients not included in model building.

Results: Mean (range) age of the 53 model-building subjects was 7.8 years (0.2-19.0 years) and weight was 26.5 kg (5.6-78.0 kg), similar to nearly 120 validation subjects. There were 16.7 samples (6-26 samples) per subject to build the model. The BestDose cohort was also diverse: 10.2 years (0.25-18 years) and 46.4 kg (5.2-110.9 kg). Mean bias and imprecision of the 1-compartment model-predicted busulfan concentrations were 0.42% and 9.2%, and were similar in the validation cohorts. Initial dosages to achieve average concentrations of 600-900 ng/mL were 1.1 mg/kg (≤12 kg, 67% in the target range) and 1.0 mg/kg (>12 kg, 76% in the target range). Using all 9 concentrations after dose 1 in the Bayesian estimation of dose requirements, the mean (95% confidence interval) bias of BestDose calculations for the third dose was 0.2% (-2.4% to 2.9%, P = 0.85), compared with the standard noncompartmental method based on 9 concentrations. With 1 optimally timed concentration 15 minutes after the infusion (calculated with the authors' novel MMopt algorithm) bias was -9.2% (-16.7% to -1.5%, P = 0.02). With 2 concentrations at 15 minutes and 4 hours bias was only 1.9% (-0.3% to 4.2%, P = 0.08).

Conclusions: BestDose accurately calculates busulfan intravenous dosage requirements to achieve target plasma exposures in children up to 18 years of age and 110 kg using only 2 blood samples per adjustment compared with 6-9 samples for standard noncompartmental dose calculations.

Figure 1

Relationship between (top) KeS (elimination adjusted allometrically for body size) and (bottom) VS (volume adjusted allometrically for body size) and age. Equations for the polynomials are shown in the legend for Table 4.

Figure 2

Marginal plots of population parameter value distributions for busulfan KeS (elimination adjusted allometrically for body size and age) and VS (volume adjusted allometrically for body size and age).

Figure 3

Visual predictive check for the final model. Circles are measured concentrations, the lower and upper lines are the 2.5^th and 97.5^th percentiles of simulated concentrations, and the central line is the median of the simulated concentrations.

Figure 4

Residual plot for the model predictions, based on the median population parameter values. In the residual plot, there is a tendency to slightly underpredict later concentrations as seen in the middle panel. In the right panel is shown a histogram of the residuals with an ideal normal distribution as a dashed line.

Figure 5

Observed vs. predicted plots for busulfan. Predictions were based on the median population parameter values (left) or the medians of the individual Bayesian posterior parameter values (right).