A Physiologically Based Pharmacokinetic Model to Predict Potential Drug–Drug Interactions of TPN171 , a Novel Phosphodiesterase Type 5 Inhibitor

TPN171 is a potent phosphodiesterase type 5 inhibitor used to treat pulmonary arterial hypertension and erectile dysfunction, primarily metabolized by CYP3A4. This study aimed to evaluate its drug–drug interaction (DDI) potential and determine the optimal dosing when co‐administered with CYP3A4 modulators. A physiologically based pharmacokinetic (PBPK) model was developed and validated using clinical DDI data for itraconazole (strong CYP3A4 inhibitor) and rifampin (strong CYP3A4 inducer). The model was then applied to predict DDIs with moderate (diltiazem, fluconazole) and mild (fluvoxamine) inhibitors, as well as moderate (efavirenz) and mild (zanubrutinib) inducers. Predicted AUC 0−t ratios aligned with observed data: itraconazole (2.42‐fold predicted vs. 2.67‐ fold observed) and rifampicin (0.14‐fold predicted vs. 0.096‐fold observed). For other modulators, geometric mean AUC 0−t ratios were 2.40 with diltiazem, 3.27 with fluconazole (400 mg), 2.07 with fluconazole (100 mg), 1.16 with fluvoxamine, 0.53 with efavirenz, and 0.70 with zanubrutinib. These simulations indicate that strong and moderate CYP3A4 inhibitors and inducers significantly alter TPN171 exposure, whereas weak modulators have no clinically meaningful impact. These findings provide a scientific basis for dose recommendations when TPN171 is used with CYP3A4 modulators.