A Mechanism-Based Multi-Level Population PK/PD Model for Potassium-Competitive Acid Blockers

Area of Science:

• Pharmacology
• Pharmacokinetics and Pharmacodynamics
• Drug Development

Background:

• Potassium-competitive acid blockers (PCABs) are emerging treatments for acid-related diseases, offering an alternative to proton pump inhibitors.
• Optimizing PCAB dosing is challenging due to complex interactions between drug exposure, food intake, and circadian rhythms.
• Understanding these interactions is crucial for effective pharmacotherapy.

Purpose of the Study:

• To develop and apply a multi-level population pharmacokinetic/pharmacodynamic (PK/PD) model for four representative PCABs: tegoprazan, YH4808, fexuprazan, and vonoprazan.
• To evaluate cross-drug PK/PD variability and the impact of food intake on PCAB efficacy.
• To provide a modeling platform for optimizing PCAB dosing strategies and informing drug development.

Main Methods:

• A semi-mechanistic population PK/PD model was constructed using published data, incorporating food effects, circadian pH rhythms, and pH-dependent absorption.
• A multi-level nonlinear mixed-effects modeling framework was employed to analyze inter-drug and inter-study variability.
• Simulations were performed to predict intragastric pH profiles and assess the impact of meal timing on acid control.

Main Results:

• The model accurately described plasma concentrations and intragastric pH for all four PCABs under various conditions.
• Significant differences in PK and PD potency were identified among the PCABs, with in vitro potency ranked as vonoprazan > fexuprazan > YH4808 > tegoprazan.
• Both pre- and post-meal administration were shown to enhance gastric pH control, with distinct mechanisms potentially involved depending on dosing conditions.

Conclusions:

• The study successfully demonstrated a mechanistic, multi-level population approach for cross-drug PK/PD evaluation of PCABs.
• Findings support the need for drug-specific dose optimization, highlighting the clinical significance of food-drug interactions in PCAB therapy.
• The developed modeling framework serves as a valuable tool for pharmacotherapy and model-informed drug development (MIDD).