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

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. AIMS The aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection. METHODS Patients 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. RESULTS Rabeprazole 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. Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain. In contrast, in CYP2C19 EMs the eradication rates ranged from 58 to 85%. CONCLUSIONS CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PMs for H. pylori eradication. [ABSTRACT FROM AUTHOR]