Evaluation of drug-drug interaction potentials between JP-1366 and celecoxib using physiologically based pharmacokinetic modeling

Zastaprazan (JP-1366) is a new potassium-competitive acid blocker being developed for treating gastrointestinal reflux disease. It is an orally administered small molecule that inhibits gastric H+ and K+-ATPases differently from proton pump inhibitors, which act quickly and have dose-dependent effects on acid secretion. Celecoxib, a selective cyclooxygenase 2 inhibitor, will likely be used with zastaprazan in clinical settings and trials. The objective of current physiologically based pharmacokinetic (PBPK) modeling study is to predict drug-drug interaction (DDI) risk between zastaprazan (perpetrator) and celecoxib (victim). A human PBPK model for zastaprazan was built using experimental physicochemical properties and <i>in silico</i> predictions. The model was optimized with clinical pharmacokinetic (PK) data from a phase 1 study (Protocol No. JP-1366-105). The PBPK model for celecoxib was constructed using the data from previous studies and <i>in silico</i> predictions. The final PBPK model encompassing zastaprazan and celecoxib was used to quantitatively predicted DDI risks in humans. The final PBPK models accurately predicted zastaprazan's PK profiles after single dose in human, and it also well predicted plasma celecoxib concentrations over time. At doses of 20 mg of zastaprazan citrate (JAQBO^® tablet) and 200 mg of celecoxib, multiple oral doses of zastaprazan every 24 hours for 7 days did not increase celecoxib's area under the curve (AUC) and maximum plasma concentration (C_max), with ratios of 1 in both AUC and C_max, indicating no effect of zastaprazan on celecoxib's PK. The PBPK modeling approach provides scientific predictions of DDIs between zastaprazan and celecoxib, guiding future clinical development.