CYP3A4 and chronic obstructive pulmonary disease: Specially, the PBPK model was used to (i) predict the area under the curve (AUC) and maximum concentration (Cmax) of ROF and ROF N-oxide in healthy individuals and in COPD patients; (ii) predict PK- and PD-related DDIs of ROF when used in combination with eight CYP3A4 and CYP1A2 perpetrators, respectively; and (iii) recommend an optimal dosing regimen for DDIs.