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: