External Evaluation of Population Pharmacokinetic Models of Busulfan in Chinese Adult Hematopoietic Stem Cell Transplantation Recipients

Objective: Busulfan (BU) is a bi-functional DNA-alkylating agent used in patients undergoing hematopoietic stem cell transplantation (HSCT). Over the last decades, several population pharmacokinetic (pop PK) models of BU have been established, but external evaluation has not been performed for almost all models. The purpose of the study was to evaluate the predictive performance of published pop PK models of intravenous BU in adults using an independent dataset from Chinese HSCT patients, and to identify the best model to guide personalized dosing. Methods: The external evaluation methods included prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. In prediction-based diagnostics, the relative prediction error (PE%) was calculated by comparing the population predicted concentration (PRED) with the observations. Simulation-based diagnostics included the prediction- and variability-corrected visual predictive check (pvcVPC) and the normalized prediction distribution error (NPDE). Bayesian forecasting was executed by giving prior one to four observations. The factors influencing the model predictability, including the impact of structural models, were assessed. Results: A total of 440 concentrations (110 patients) were obtained for analysis. Based on prediction-based diagnostics and Bayesian forecasting, preferable predictive performance was observed in the model developed by Huang et al. The median PE% was -1.44% which was closest to 0, and the maximum F(20) of 57.27% and F(30) of 72.73% were achieved. Bayesian forecasting demonstrated that prior concentrations remarkably improved the prediction precision and accuracy of all models, even with only one prior concentration. Conclusion: This is the first study to comprehensively evaluate published pop PK models of BU. The model built by Huang et al. had satisfactory predictive performance, which can be used to guide individualized dosage adjustment of BU in Chinese patients.