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

Summary 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.