Assessments of CYP-inhibition-based drug-drug interaction between vonoprazan and poziotinib in vitro and in vivo

Context Poziotinib and vonoprazan are two drugs mainly metabolized by CYP3A4. However, the drug-drug interaction between them is unknown. Objective To study the interaction mechanism and pharmacokinetics of poziotinib on vonoprazan. Materials and methods In vitro experiments were performed with rat liver microsomes (RLMs) and the contents of vonoprazan and its metabolite were then determined with UPLC-MS/MS after incubation of RLMs with vonoprazan and gradient concentrations of poziotinib. For the in vivo experiment, rats in the poziotinib treated group were given 5 mg/kg poziotinib by gavage once daily for 7 days, and the control group was only given 0.5% CMC-Na. On Day 8, tail venous blood was collected at different time points after the gavage administration of 10 mg/kg vonoprazan, and used for the quantification of vonoprazan and its metabolite. DAS and SPSS software were used for the pharmacokinetic and statistical analyses. Results In vitro experimental data indicated that poziotinib inhibited the metabolism of vonoprazan (IC50 = 10.6 mu M) in a mixed model of noncompetitive and uncompetitive inhibition. The inhibitory constant K-i was 0.574 mu M and the binding constant alpha K-i was 2.77 mu M. In vivo experiments revealed that the AUC((0-) (T) ()) (15.05 vs. 90.95 mu g/mL center dot h) and AUC((0-infinity)) (15.05 vs. 91.99 mu g/mL center dot h) of vonoprazan increased significantly with poziotinib pretreatment. The MRT(0-infinity) of vonoprazan increased from 2.29 to 5.51 h, while the CLz/F value decreased from 162.67 to 25.84 L/kg center dot h after pretreatment with poziotinib. Conclusions Poziotinib could significantly inhibit the metabolism of vonoprazan and more care may be taken when co-administered in the clinic.