Physiologically based pharmacokinetic (PBPK) modeling of drug-drug interactions between suraxavir marboxil and CYP3A4 inhibitors: Quantitative prediction of pharmacokinetic effects on active metabolite GP1707D07

Suraxavir marboxil (GP681) is a promising novel prodrug influenza polymerase acidic (PA) inhibitor whose active metabolite, suraxavir (GP1707D07), is primarily metabolized by cytochrome P450 3A4 (CYP3A4), raising concerns about drug-drug interactions (DDI) with CYP3A4 inhibitors. Traditional DDI assessment methods are limited for evaluating all potential combinations. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDI risk between GP681 and CYP3A4 inhibitors of varying potency. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including a phase I single ascending dose study of GP681 tablets and a single-center phase I study evaluating the DDI between GP681 and strong CYP3A4 inhibitor itraconazole. The model was successfully verified against clinical data, with predicted-to-observed ratios for GP1707D07 exposure under itraconazole co-administration of AUC and C_max of 1.042 and 1.357, respectively. Simulations using the validated model predicted a substantial increase in GP1707D07 exposure when co-administered with moderate inhibitors fluconazole (AUC ratio 2.820; C_max ratio 1.509) and verapamil (AUC ratio 2.347; C_max ratio 1.645), comparable to the effect of itraconazole. Weak inhibitors showed negligible effects. Consequently, clinical monitoring and potential dose adjustment of GP681 are recommended when co-administered with strong inhibitors and the moderate inhibitors. The study demonstrates the utility of PBPK modeling for efficient and predictive DDI assessment of complex prodrug systems, guiding the safe clinical use of GP681.