When patients carried the GSTA1 *A/*B mutation, GSTA1 = 1, and when patients carried the *A/*A genotype, GSTA1 = 0.
Population estimates for a patient with median BSA with GSTA1 *A/*A were CL 4.79 L/h and V 14.8 L. The values of inter-individual variability for CL and V were 18.65% and 23.63%, respectively. CL of patients carrying the GSTA1 *A/*B genotype was predicted to decline by 17.3% compared with those carrying GSTA1 *A/*A . As a result, CL/BSA between two genotypes had a significant difference (p = 0.0103), in spite of AUC/BSA without significant difference (Figure 1 ).
3.3 Model evaluation and validation
Shrinkage values of clearance and volume were respectively 0.207 and 0.130, which manifested that the model-building dataset was rich enough to compute the PK parameters of busulfan in children.
Compared with the base model, the -2LL value of final model declined by 175.26, which indicated that the model improved substantially after incorporating covariates, BSA, AST and GSTA1 phenotype. As demonstrated in the scatter plots of OBS vs. PRED (Figure 2A and 2B ), the PRED strongly deviated from the OBS in the base model, but PRED agreed with the OBS in the final model. In addition, the CWRES in the final model were more uniformly distributed within the accepted range (y = ± 2) than that in the base model (Figure 2C and 2D ). As a whole, the final model was visually improved in terms of the GOF and had a more accurate predictive performance.
The estimated values generated by bootstrap analysis were close to the parameters in the final model, which also fell within 95% CIs (Table 3 ). Thus, it can be considered that the final model was accurate and robust. Figure 3 clearly displayed that 5th, 50th and 95th percentiles of simulation values almost coincided with that of observed concentrations. The results of VPC combined with bootstrap analysis confirmed the exactitude of the parameter estimates and demonstrated the reliability of the final model. For external validation, a mean difference of 18.48% was observed in the simulated Bu concentrations generated using the established PPK model when compared with the observed Bu concentrations (Figure 4 ).
3.4 New dosing strategy and simulations
To achieve a target AUC of 1125 μM·min, a simple linear relationship between the total doses and BSA is illustrated in Figure 5(A). The linear Equation 7 and 8 for GSTA1 *A/*A and *A*B was respectively: