Characterization of plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders

Abstract

Factors that determine clinical responses to vonoprazan remain unknown. This study aimed to characterize plasma vonoprazan and CYP3A activity using its endogenous marker and genetic variants in patients with digestive system disorders. Fifty-three patients who were receiving vonoprazan for at least 3 days were enrolled. Blood samples for determination of plasma vonoprazan and its metabolite (ODA-VP) were obtained. Plasma 4β-hydroxycholesterol (4β-OHC), CYP3A5 and ABCB1 genotypes, and plasma gastrin were determined. CYP3A recognition for vonoprazan was evaluated using recombinant CYP3A proteins. Plasma vonoprazan levels exhibited a large interindividual variation. The absolute plasma concentration of vonoprazan was correlated with its dose-normalized value, and had a positive correlation with the inverse value of its metabolic ratio. A negative correlation was observed between plasma vonoprazan and 4β-OHC levels. The metabolic ratio of vonoprazan was positively correlated with the plasma 4β-OHC level. Genetic variants of CYP3A5 and ABCB1 were not associated with the plasma concentration of vonoprazan and its metabolic ratio. Possible saturated metabolism of vonoprazan to its major metabolite was observed at a therapeutic dose. Although the CYP3A5 genotype did not alter plasma vonoprazan, CYP3A activity based on plasma 4β-OHC partially explained the variation in plasma vonoprazan in patients with digestive system disorders.

Keywords: 4β-hydroxycholesterol; CYP3A4; Gastrin; Pharmacokinetics; Vonoprazan.