Evaluation and validation
The addition of covariates greatly improved the stability of model, as a result, the OFV decreased from 1774.00 (base model) to 1673.89 (final model). The observation versus population and individual predictions (Figure 6A, B) were generally evenly distributed around the identity line, except for some positive bias at high concentrations, indicating a good model fitting. Of the conditional weighted residuals (CWRES) versus time after dose and population predictions (Figure 6C, D), the CWRES were symmetrically distributed around y=0 line and mostly within ±2 unit, confirming that the model has a good accuracy. The population typical value of final model closely agreed with mean estimated from bootstrap and is within 95% CI, which demonstrate that the model prediction is accurate and stability (Table 2). According to VPC (Figure 7), the major observations was distributed within 95% CI of simulated values, indicating a good predictive performance of final model.