Zastaprazan citrate

Zastaprazan is a potent potassium-competitive acid blocker developed to treat gastroesophageal reflux disease. The aim of this study was to evaluate the efficacy and safety of zastaprazan compared with esomeprazole in patient with erosive esophagitis (EE).

A phase III, multicenter, randomized, double-blind, noninferiority clinical study was conducted with 300 subjects with confirmed EE. Subjects were randomized to receive zastaprazan 20 mg or esomeprazole 40 mg once daily up to 8 weeks. The primary end point was the cumulative proportion of subject with healed EE confirmed by endoscopy at week 8. The secondary end points included the healing rate at week 4, symptom response, and quality of life assessment. Safety profiles and serum gastrin levels were also assessed.

In the full analysis set, the cumulative healing rate at week 8 were 97.92% (141/144) for zastaprazan and 94.93% (131/138) (P = 0.178) for esomeprazole. The healing rate at week 4 in the zastaprazan group was higher than the esomeprazole group (95.14% [137/144] vs 87.68% [121/138]; P = 0.026). There was no significant difference between groups in healing rates (the per-protocol set) at week 8 and week 4, symptom responses, quality of life assessments, and safety profiles. In addition, serum gastrin levels increased during treatment in both groups, with a significant difference between the 2 groups (P = 0.047), but both decreased after treatment.

An 8-week therapy of zastaprazan 20 mg is noninferior to esomeprazole 40 mg in subjects with predominantly low-grade EE. The healing rate at week 4 appears to be higher for zastaprazan than esomeprazole.

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 in silico 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 in silico 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.