Application of pharmacokinetic and pharmacodynamic analysis to support the selection of a 40 mg dose for the immediate-release omeprazole formulation in PA32540

Objectives: An investigational product was designed to release IR omeprazole into the stomach, followed by EC aspirin released when the gastrointestinal tract pH exceeds 5.5.  Data are limited to determine a gastroprotective dose for immediate-release (IR) omeprazole to be combined with enteric-coated (EC) aspirin in a single tablet intended for patients at risk of aspirin-induced gastric ulcers. 

Methods: A pharmacokinetic and pharmacodynamic analysis was conducted to establish the relationship between plasma exposure to omeprazole and its effect on intragastric pH, using literature data and recent Phase 1 study results from EC omeprazole formulations. The pharmacokinetic measure was mean daily plasma exposure (AUC_0‑24) to omeprazole following once daily doses of 10 mg, 20 mg, or 40 mg EC omeprazole; the pharmacodynamic measure was the mean/median percent time that gastric pH exceeds 4.0 over 24-hour continuous intragastric pH monitoring following once daily doses of 0 mg (baseline), 10 mg, 20 mg, or 40 mg EC omeprazole.

Results: The PK-PD relationship can be described by a typical pharmacological Emax model, with the maximal effect estimated as 97.5% time and the baseline effect estimated as 6.9% time with gastric pH >4.0 over 24 hours. The steady-state AUC_0‑24 of omeprazole required to achieve half the maximal response was estimated to be 2212 hr*ng/mL. This relationship was used to predict the pharmacodynamic measure from an observed AUC_0‑24 (2187 hr*ng/mL) following once daily doses of a PA32540 tablet containing 325 mg EC aspirin + 40 mg IR omeprazole to be 51.9%, which is consistent with the observed 50.5% time with gastric pH >4.0.

Conclusion: A lower IR omeprazole dose (20 mg) in the combination tablet would produce only 33.9% time with gastric pH >4.0 over 24 hours, which may be suboptimal for gastric mucosal protection.  The PK-PD analysis supports a 40 mg IR omeprazole dose.