Simcyp version 17

All simulations were performed using the PBPK modeling software Simcyp version 17 (Certara, Princeton, NJ). The models for dextromethorphan, dextrorphan, tolterodine, and fluoxetine were used as provided by the software and modified if required using available clinical data (see Data S1). A model for duloxetine was built based on available in vitro and clinical data. The risperidone model was taken from Vieira et al.13 All simulations used for model verification perform 10 trials of a given number of subjects.

All simulations were performed using Simcyp version 17 (Certara, Princeton, NJ). Noncompartmental analyses were carried out using Phoenix WinNonlin version 6.4 (Certara, Princeton, NJ). All major atorvastatin‐related species (atorvastatin, o‐hydroxyatorvastatin, atorvastatin lactone, and o‐hydroxyatorvastatin lactone) were included in the model. To incorporate the gastric conversion of atorvastatin to atorvastatin lactone, two model files were created, one for atorvastatin and one for atorvastatin lactone, to represent lactone formation in the stomach. The fraction of atorvastatin absorbed as acid/lactone at each atorvastatin dose was determined as described in Model Files below. The species included in each model file and the inputs are summarized in Table 1. Figure 1 depicts the generalized disposition of all species included in the current model and the overall modeling strategy.