Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) developed by CJ Healthcare (Korea) for the treatment of gastroesophageal reflux disease and helicobacter pylori infections. Tegoprazan is mainly metabolized by cytochrome P450 (CYP) 3A4. Considering the therapeutic indications, tegoprazan is likely to be administered in combination with various drugs. Therefore, the investigation of drug-drug interactions (DDI) between tegoprazan and CYP3A4 perpetrators is imperative. In the present study, we first aimed to develop a physiologically based pharmacokinetic (PK) model for tegoprazan and its major metabolite, M1, using PK-Sim. This model was applied to predict the DDI between tegoprazan and CYP3A4 perpetrators. Clarithromycin, a potent inhibitor of CYP3A4, and rifampicin, a strong inducer of CYP3A4, were selected as case studies. Our results show that clarithromycin significantly increased the exposure of tegoprazan. The area under the concentration-time curve () and of tegoprazan in the steady state increased up to 4.54- and 2.05-fold, respectively, when tegoprazan (50 mg, twice daily) was coadministered with clarithromycin (500 mg, three times daily). Rifampicin significantly reduced the exposure of tegoprazan. The and of tegoprazan were reduced by 5.71- and 3.51-fold when tegoprazan was coadministered with rifampicin (600 mg, once daily). Due to the high DDI potential, the comedication of tegoprazan with CYP3A4 perpetrators should be controlled. The dosage adjustment for each individual is suggested.