The first-order conditional estimation with interaction (FOCE-I) in NONMEM was used for all runs.
The model fits were based on visual inspection of goodness-of-fit (GOF) plots, OFV, parameter precision, and shrinkage values. The robustness of the parameter estimates and the validity of the models were evaluated with a bootstrap analysis (n=1000) and a visual predictive check (VPC), respectively. Data handling, visualization and descriptive statistics were performed using Pirana
(v2.9.4 Certara, Radnor, PA, USA), R Studio version 4.3.1 and GraphPad Prism 9.0 (GraphPad Software, Boston, Massachusetts, USA).