減少CYP2C19基因多型性影響esomeprazole在GERD治療的最佳給藥療程之研究與開發

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

陳瑩真(Ying-Chen Chn)

指導教授 ： 許明照

臺北醫學大學/藥學院/藥學研究所/碩士(2007年)

摘要

背景：氫離子幫浦阻斷劑是胃食道逆流性疾病的首選藥物，大多數的病人在治療後可復原，卻有10-20%病人無法獲得改善；這種治療上的個體差異可能是因為CYP2C19基因多型性的影響。

目的：為了改善治療效果，本實驗有三個目的 (1) 觀察基因多型性和不同給藥療程對esomeprazole抑制胃酸的影響；(2) 建構esomeprazole藥物動力學和藥物治療學關係；(3) 發展出一最適治療胃食道逆流性疾病療程以適合所有基因多型性的人。

方法：共有38位受試者參與CYP2C19基因多型性篩選，依照基因篩選方法 (PCR-RFLP) 可分成三種基因族群：分別是代謝快速、代謝中等和代謝緩慢族群；在各基因族群中隨機挑選三名沒有胃幽門螺旋桿菌感染的受試者參加藥物人體試驗，以觀察CYP2C19 基因多型性與esomeprazole 藥物動力學和治療學上的影響，並比較不同esomeprazole治療療程 (1)一天一次，每次40公絲；(2) 一天兩次，每次20公絲；(3)一天四次，每次10公絲；各療程持續七天，在每一療程的第七天觀察藥物動力學和治療學上的關係。在本試驗中，藥物動力學是收集特定時間點血漿，利用高效率液相層析法分析esomeprazole濃度；藥物治療學是利用鼻胃導管，偵測24小時胃酸酸鹼值。

結果和討論：由基因篩選結果得知，在本試驗中，CYP2C19代謝快速族群的比例最高，但與其他西方文獻相比，本次代謝緩慢的族群比例較西方人多，由此推論，西方國家的CYP2C19代謝快速族群比率較東方國家多，因此使用經由CYP2C19代謝的藥物，其療效和副作用在不同種族間可能會有差異性。由藥物人體臨床試驗結果看來CYP2C19代謝快速的族群，其藥物血中濃度較低且抑制胃酸分泌效果較代謝緩慢族群差，因此藥物動力學參數和胃酸酸鹼值與基因影響密切；這可能是因為esomeprazole主要是經過CYP2C19代謝，未突變的CYP2C19基因，其酵素活性較突變的CYP2C19強，所以esomeprazole代謝增多，造成血中濃度降低，因此療效下降。另外，在相同藥物劑量下，單次給藥(即一天一次)無法達到理想治療效果，而較頻繁的給藥 (即一天兩次和一天四次給藥)在抑制胃酸分泌方面有良好效果；可能是因為頻繁給藥能持續維持一平穩的血中濃度，因此不只對當時也對後續的胃酸分泌都能達到抑制的效果。

結論：由此試驗結果得知，esomeprazole藥物動力學和治療學受CYP2C19基因多型性影響，而較頻繁的給藥，即一天兩次，每次20公絲esomeprazole可以對所有基因多型性族群都維持良好的治療效果。

關鍵字

CYP2C19基因多型性，胃食道逆流性疾病，氫離子幫浦阻斷劑，esomeprazole，夜間胃酸突增

並列摘要

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.

並列關鍵字

CYP2C19 polymorphism，Gastroesophageal reflux disease，proton pump inhibitors，esomeprazole，nocturnal gastric acid breakthrough

參考文獻

1.Storr M, Meining A: Pharmacologic management and treatment of gastroesophageal reflux disease. Diseases of the Esophagus 2004, 17(3):197-204.

3.Robinson M: Review article: The pharmacodynamics and pharmacokinetics of proton pump inhibitors - Overview and clinical implications. Alimentary Pharmacology and Therapeutics, Supplement 2004, 20(6):1-10.

4.Bell NJV, Burget D, Howden CW, Wilkinson J, Hunt RH: Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion 1992, 51(SUPPL. 1):59-67.

5.Stedman CAM, Barclay ML: Review article: Comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Alimentary Pharmacology and Therapeutics 2000, 14(8):963-978.

6.Pisegna JR: Pharmacology of acid suppression in the hospital setting: Focus on proton pump inhibition. Critical Care Medicine 2002, 30(6 SUPPL.).