THRESHOLD BLOOD OMEPRAZOLE CONCENTRATION IS 50 NG/ML FOR THE MAINTENANCE OF INTRAGASTRIC pH OF AT LEAST 4.0 AFTER ORAL DOSING WITH CMA-OMEPRAZOLE, AGN 201904-Z
AMERICAN JOURNAL OF GASTROENTEROLOGY(2007)
摘要
Purpose: To determine the threshold blood omeprazole concentration for the maintenance of intragastric pH of at least 4.0 after oral dosing with AGN 201904-Z, an acid-stable, chemically metered absorption derivative of omeprazole (CMA-omeprazole). Methods: Forty healthy male subjects received 240, 480, and 640 mg AGN 201904-Z and 40 mg esomeprazole orally once-daily for 5 days in a open-label, randomized, 4-way cross-over study. These doses were estimated to deliver molar equivalent omeprazole doses of 53%, 107%, and 143% of the esomeprazole dose, respectively. Pharmacokinetic (PK) blood samples were collected at 8 timepoints following the 1st and 5th dose of each treatment. Pharmacodynamics (PD) were evaluated via 24-hr intragastric pH monitoring before treatment and after the 1st and 5th doses of each treatment. Empirical PK/PD models were constructed for AGN 201904-Z data by regressing the%time that intragastric pH ≥4.0 during a 24-hr dosing period against the duration of time that blood omeprazole concentrations were greater than 8 different concentrations over the same 24-hr period. The possible threshold concentrations evaluated ranged from 10 to 400 ng/mL. The concentration that provided the best-fit was designated the threshold concentration. The best-fit concentration and model was chosen based on WSSR, R2, visual inspection, and AIC value. Results: Among the possible omeprazole threshold concentrations evaluated, 50 ng/mL was the best-fit concentration value in all of the models evaluated. The final model suggests the%time intragastric pH ≥4.0 is dependent on the duration of time that blood omeprazole concentrations are maintained above 50 ng/mL. This agreed with the actual results which showed AGN 201904-Z maintained drug concentrations above 50 ng/mL longer than esomeprazole (18.0 vs. 9.2 hr), and also maintained intragastric pH ≥4.0 longer than esomeprazole (80.1 vs. 68.4% of 24-hr; p < 0.0001). Conclusions: The 50 ng/mL blood omeprazole concentration provided the best correlation with the percent time intragastric pH was ≥4.0 over a 24-hr dosing interval and was designated as the threshold concentration of omeprazole. AGN 201904-Z, a CMA-omeprazole designed to provide sustained omeprazole exposure, was more effective than esomeprazole at maintaining 24-hour intragastric pH ≥4.0.
更多查看译文
关键词
threshold blood omeprazole concentration,intragastric,oral dosing,cma-omeprazole
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要