Pharmacokinetic– pharmacodynamic analysis of the role of CYP2C19 genotypes in short‐term rabeprazole‐based triple therapy against Helicobacter pylori

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Asians have a higher percentage of CYP2C19 poor metabolizers (PMs) and a high percentage of Helicobacter pylori infection compared with Whites.• Although rabeprazole has been suggested to be least affected by CYP2C19 genotype, the pharmacokinetic properties of rabeprazole have been shown to correlate with the CYP2C19 genotype. • Short-term (i.e. <7 days) rabeprazole-based triple therapy has been suggested for its use in eradicating H. pylori, whereas the eradication rate has been reported variously as 90-27% without CYP2C19 genotyping. WHAT THIS STUDY ADDS• Population pharmacokinetic-pharmacodynamic analysis showed that the plasma rabeprazole levels, the values of keo (the first-order rate constant for drug dissipation from the effect compartment), and the predicted gastrin-time profile were higher in CYP2C19 PMs than in extensive metabolizers (EMs) after multiple dosing.• Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain, whereas the eradication rates ranged from 58 to 85% in CYP2C19 EMs. AIMSThe aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection. METHODSPatients with H. pylori infection were tested for CYP2C19 genotype as poor metabolizers (PMs) or extensive metabolizers (EMs, homozygous EM or heterozygous EM) and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1-4, days 4-7, or days 1-7. A direct link model with an effect compartment was used in the population pharmacokinetic-pharmacodynamic analysis. The status of H. pylori infection was evaluated. RESULTSRabeprazole clearance was lower in CYP2C19 PMs than in EMs (with average values of 10.7 vs. 16.8 l h -1 in PMs and EMs, respectively), resulting in higher plasma levels in the former group. The values of EC50 and keo of gastrin response increased with multiple doses of rabeprazole. The keo values were lower in CYP2C19 PMs than in EMs on day 1 (0.012 vs. 0.017 ¥ 10 -4 l min -1 ), and higher than in EMs on day 4 (0.804 vs. 0.169 ¥ 10 -4 l min -1 ) of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PMs than in EMs on days 4 and 7.

Role of Omeprazole Dosage and Cytochrome P450 2C19 Genotype in Patients Receiving Omeprazole‐Amoxicillin Dual Therapy for Helicobacter pylori Eradication

“…29,30 Since most proton pump inhibitors are mainly metabolized by CYP2C19, the CYP2C19 poor metabolizers should have a higher proton pump inhibitor concentration and a better acid inhibition response after receiving proton pump inhibitors. 17,31 The cure rate for H. pylori infection has been reported to be significantly different among patients of different CYP2C19 genotypes. 32,33 In our study, although the cure rate could not be statistically differentiated between homozygous and heterozygous extensive metabolizers because of limited sample size, it was noted that heterozygous extensive metabolizers tended to be more responsive to the higher omeprazole dose than were homozygous extensive metabolizers.…”

The Influence of CYP2C19 Polymorphism on Eradication of Helicobacter pylori: A Prospective Randomized Study of Lansoprazole and Rabeprazole

“…9 Several trials have been published concerning the effect of the CYP2C19 genotype on eradication of H. pylori by various PPIs-based therapies. [10][11][12][13][14][15] However, there are few data available on the direct comparison of eradication rate of rabeprazole with other PPIs considering CYP2C19 polymorphism. With the previously mentioned backgrounds in mind, we aimed to know the influence of CYP2C19 on eradication of H. pylori with rabeprazole or lansoprazole.…”

Assessment of Helicobacter pylori positive infected patients according to Clarithromycin resistant 23S rRNA, rpl22 associated mutations and cyp2c19*1, *2, *3 genes pattern in the Early stage of Gastritis

“…Proton pump inhibitors (PPIs) covalently interact with the cysteine residue of proton pumps which inhibit H + releases, thereby collaboration of PPIs in prescription promotes stability and concentration of Clarithromycin. P450 CYP 2c19 is the liver catabolic enzyme that dominantly corresponds to the metabolization of omeprazole and lansoprazole [5][6][7]. Among 34 cyp2c19 allele polymorphisms distinct for the deficiency in drug metabolization, there are three major losses of functions (LOF) cyp2c19*2 (681 G ≥ A), cyp2c19*3(636 G ≥ A), and cyp2c19*17 (806 C ≥ T) in which cyp2c19*2 and cyp2c19*3 are mainly reputed in Asian population than cyp2c19*17 for less than 1% [7].…”