Development of an optimal dose regimen of esomeprazole for GERD with minimal influence of CYP2C19 polymorphism

• Main Authors: Ying-Chen Chn, 陳瑩真
• Other Authors: 許明照
• Format: Others
• Language: en_US
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/57002232876051605009

碩士 === 臺北醫學大學 === 藥學研究所 === 95 === Background: Proton pump inhibitors have been the most effective treatment for gastroesophageal reflux disease. However, there is approximately 10-20% of patients have failed to this medication. This inter-indiviual variety may be due to CYP2C19 polymorphism. Purposes：To improve this insufficient acid suppression, we aimed to (1) find the impact of CYP2C19 polymorphism and different dosage regimens on acid inhibition with esomeprazole； (2) construct a relationship between pharmacokinetics and pharmacodynamics of esomeprazole; (3) develop an optimal dosage regimen for GERD regardless of CYP2C19 genotypes. Methods: There are 38 subjects participated CYP2C19 genotyping. At last, nine Helicobacter pylori–negative volunteers, comprising 3 homozygous extensive metabolizers (homEMs), 3 heterozygous EMs (hetEMs), and 3 poor metabolizers (PMs) of CYP2C19 determined by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to compare the impact of CYP2C19 polymorphism on pharmacokinetics and pharmacodynamics with esomeprazole, completed this clinical trial. Subjects were given predose and esomeprazole, at a dose of 40 mg once daily (at 8AM), 20 mg twice daily (at 8AM and 6PM), and 10 mg 4 times daily (at 8AM, 12PM, 6PM, and 10PM) for 7 days to observe the influence of different dosage regimens on pharmacokinetics and pharmacodynamics. On day 7 of each regimen, subjects were determined pharmacokinetic data, plasma esomeprazole concentrations analyzed by HPLC; and pharmacodynamic data, 24-hour intragastric pH recorded by a pH meter. Results and discussion: The ratio of homEM in this study was the highest, but the ratio of PMs in the population was higher than that in Western. There exist marked ethnic differences in the incidence of this polymorphic deficiency in Oriental and Western. Furthermore, the therapeutic effect and side effect of CYP2C19 substrate drug may be diverse between different populations. The Cmax and anti-secretary effect were lowest in homEMs, this is because esomeprazole metabolized rapidly, mainly by CYP2C19, therefore, not sufficient to achieve effective plasma esomeprazole concentration of gastric acid suppression for homEMs. With 40 mg esomeprazole once daily, the gastric acid suppression is not sufficient to achieve therapeutic effect. With 20 mg twice daily or 10 mg 4 times daily, was found to be as effective in controlling both daytime and nocturnal gastric acidity for all of the three genotypes. With multiple dosing, however, plasma esomeprazole concentrations were sustained throughout the 24-hour period, suggesting that newly generated after the rapid elimination of esomeprazole can be inactivated consistently by subsequent dose. Conclusions: We proposed that the intragastric pH values and the plasma esomeprazole concentrations depended on CYP2C19 genotype status. Divided doses of 40 mg esomeprazole daily (ie, 20 mg twice daily or 10 mg 4 times daily) yielded excellent anti-secretary effect with minimal influence of CYP2C19 polymorphism.