A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection

Background: Treatment of acid--related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH > 4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium--competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. Aim: To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. Methods: We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct--link PK/PD models were derived and used to simulate pH HTRs with between--participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. Results: We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non--Asian). Pre-dose, the mean pH > 4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. Conclusions: Vonoprazan 20 mg once--and twice--daily dosing demonstrated high, dose--dependent, 24--hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid--related disorders.

Automated summary

This study explored the relationship between vonoprazan exposure and intragastric pH using a pharmacokinetic/pharmacodynamic (PK/PD) model. The results showed that vonoprazan at doses of 20 mg once and twice daily effectively controlled gastric acid secretion, supporting the clinical efficacy data in patients with acid-related disorders.