Optimal dose regimens of esomeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism

Abstract

It was confirmed that intragastric pH values and plasma esomeprazole concentrations potentially depended on the CYP2C19 genotype status for treatment with esomeprazole. Dosage regimens of divided doses of 20TD or 10Q4D esomeprazole yielded improved antisecretory effects with a minimal influence of CYP2C19 polymorphisms.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…Similarly, the AUC following the administration of equal doses of pantoprazole in PM was sixfold higher than NM and IM [43,44]. Although reports have documented the impact of CYP2C19 genotype on PK for both rabeprazole [40,45–49] and esomeprazole [50,51], these associations with PK parameters such as AUC were of smaller magnitude than the effects reported for other PPIs, suggesting less influence of CYP2C19 genotype on these newer generations PPIs. This is not surprising given that rabepeprazole and esomeprazole are less dependent on CYP2C19 for their metabolism (Table 1).…”

“…Some reports have shown that variations in acid suppression are less significant when PPIs with less CYP2C19 dependent metabolism such as rabeprazole [27,47–49] or esomeprazole [50,52,53], are administered. CYP2C19 genotype dependent variation in median gastric PH was less for esomeprazole and rabeprazole compared to omeprazole and lansoprazole [51].…”

“…Therefore, the use of higher once-daily doses or multiple daily doses of PPIs to overcome the effect of CYP2C19 genotype, has been investigated as an alternative option in individuals in whom standard doses may be insufficient to produce adequate acid suppression due to a fully functional or increased CYP2C19 activity [41,50,54]. A study by Furuta et al reported that individuals with the NM phenotype achieved an intragastric pH of 7.4 when lansoprazole 30 mg was given four times daily, suggesting that high doses of lanzoprazole may overcome the effect of genotype in individuals with NM status 41 (Table 3).…”

“…That the genotype of CYP2C19 may affect the therapeutic outcomes of PPIs was demonstrated with a string of publications documenting lower intragastric pH 48,49,50 (Table 3) with diminished control of GERD symptoms 59,60,61, and lower eradication rates of H. pylori in patients with a NM phenotype status 62,63 (Table 4). As further evidence for the impact of genotype on therapeutic outcomes, Furuta et al 60.…”

“…While an AUC ratio between PM/NM may range between 6.0 and 10 for PPIs that are extensively metabolized by CYP2C19 (omeprazole, pantoprazole and lansoprazole), this ratio is much lower (AUC PM/NM range 1.5 and 3.0) for PPIs with less CYP2C19 metabolism, such as esomeprazole and rabeprazole, respectively [45,46,50,107]. Additionally, while the CYP2C19 - inferred metabolic phenotype was consistently associated with acid suppression and therapeutic outcomes for PPIs with extensive CYP2C19 metabolism, it is not always the case with esomeprazole and rabeprazole.…”