Topiroxostat is a selective xanthine oxidoreductase (XOR) inhibitor for the management of hyperuricemia in patients with or without gout. In this work, we aim to employ the physiologically based pharmacokinetic (PBPK) model with the drug-target residence time model to predict and characterize both the pharmacokinetics (PK) and pharmacodynamics (PD) of topiroxostat in humans. The plasma concentration-time profile of topiroxostat was simulated based on drug properties and human physiology parameters. The predictive power of this PBPK model was then demonstrated by comparison of stimulated to observed pharmacokinetic parameters. The utility of the model was further demonstrated through predicting the oral absorption and disposition characteristics of topiroxostat in humans. Finally, by combining the PBPK model and the drug-target residence time model, we successfully predicted the target occupancy and built the relationship between PK and PD using in vitro, in vivo and in silico information. The results showed that topiroxostat exhibited significant in vivo pharmacological activity even after the complete clearance of this drug from the liver (target site), which may be due to the long residence time of the binary topiroxostat-XOR complex. This work may be helpful to guide future investigations of topiroxostat and also provides a novel strategy for PK/PD studies.

Many compounds with good inhibitory activity (i.e., high affinity) within in vitro experiments failed in vivo studies due to a lack of efficacy from limited target occupancy (TO) in the drug discovery process. Recently, it was found that rate constants of the formation and dissociation of the binary drug-target complex, rather than affinity, often govern in vivo efficacy. Therefore, the binding kinetics (BK) properties of compound-target interaction are emerging as a pivotal parameter. However, it is obvious that BK rate constants of the compound against target would not be directly linked to the in vivo TO unless the compound concentration in the target vicinity at any time point (TPK) can be evaluated. Here, we developed a novel simulation model to quantitate the dynamic change of target engagement over time in rat with a combined use of BK and TPK features of Epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) on the basis of α-glucosidase (AGH). Analysis of the results displayed that the percent of maximum AGH occupancies by the ECG were varied significantly from 48.9 to 95.3% and by the EGCG slightly from 96 to 99.8%; that the time course of above 70% engagement by ECG spanned a range from 0 to 0.64 h and by EGCG a range of 1.5 to 8.9 h in four different intestinal segments of the rat. It was clearly analyzed how each parameter in the simulation model effected on the in vivo the AGH engagement by ECG and EGCG. Our results provide a novel approach for assessing the potential inhibitory activity of the compounds against AGH.