Fexuprazan is a potassium-competitive acid blocker approved for treating gastric acid-related diseases. Herein, we evaluated the pharmacokinetics (PKs) of single-dose and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy subjects (Part 1) and investigated the bioequivalence between fexuprazan 10 mg and 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, 1-sequence, and 2-period design, and Part 2 comprised a single-dose, 2×2 crossover design. Eight and 23 subjects completed Parts 1 and 2, respectively. In Part 1, multiple doses accumulated twice as much as single doses. In Part 2, the geometric mean ratios [90% confidence intervals] for maximum plasma concentration (Cmax) and area under the concentration–time curve from zero to the time of the last quantifiable concentration (AUClast) of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, which met bioequivalence criteria. Overall, favorable PK was observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

The most common method for establishing bioequivalence (BE) is to demonstrate similarity of concentration-time profiles in the systemic circulation, as a surrogate to the site of action. However, the similarity, or otherwise, of profiles from two different formulation in the gastrointestinal tract (GIT) may not be associated with same conclusions based on systemic circulation. Here, we have explored the concordance of BE conclusions (or otherwise) for a set of hypothetical formulations based on drug concentration-profiles in various segments of gut vs those in systemic circulation using virtual trials powered by physiologically-based (PBPK) models. Moreover, by changing physiological and biological attributes of the GIT, the impact of Crohn’s Disease on the BE conclusions was explored. The virtual BE (VBE) was applied to an Entocort EC, a pH/time-dependent release formulation of budesonide, as model drug that is targeted at ileum and colon. Substantial “discordance” between the local and systemic outcomes of VBE was observed. Upper GIT segments were much more sensitive to formulation changes than systemic circulation, where the latter led to false conclusions for BE. The ileum and colon showed a lower frequency of discordance with systemic-derived VBE. Nonetheless, a higher f2 value than the default similarity standard (50) was required to achieve local BE. In the case of Crohn’s Disease, a product-specific f2 value might be needed for drugs such as Entocort EC to ensure local BE, knowing the insensitivity of systemic data to show lack of BE. The results, being limited to the single model drug product, Entocort EC, may not provide a a general and conclusive picture. However, for the first time, it demonstrated the potential discordances between the local gut vs systemic BE.