TQB-3909

PURPOSE: This study aimed to establish a physiologically based pharmacokinetic (PBPK) model of TQB3909 and predict the CYP3A4-mediated drug-drug interactions (DDIs) of TQB3909 to inform dosing recommendations in patients. METHODS: PBPK model was developed by integrating the physicochemical properties, in vivo and in vitro metabolic parameters of TQB3909, along with phase I clinical pharmacokinetic data and DDI clinical trial data. RESULTS: Model verification showed that the simulated drug concentrations by established PBPK model were fitted well with clinical data, with a mean fold error (MFE) ≤ 2 and most of predicted Cmax and AUC were within the range of 2-fold boundaries compared to the clinical data. Predicted Cmax and AUC geometric mean ratios (GMRs) of TQB3909 with strong CYP3A4 inhibitor itraconazole or inducer rifampicin were within 0.8 to 1.25-fold range of the observed data. DDI simulations showed that co-administration with verapamil, a moderate CYP3A4 inhibitor, increased the exposure of TQB3909 by 26%, whereas co-administration with efavirenz, a moderate CYP3A4 inducer, decreased TQB3909 exposure to 53.8% of baseline. No obvious effect of fluvoxamine (a weak CYP3A4 inhibitor) was found. CONCLUSION: This developed PBPK model effectively simulated the impact of CYP3A4 perpetrators on the pharmacokinetic behavior of TQB3909 in humans, informing clinical dose adjustment of TQB3909.