A randomized study investigating the effect of omeprazole on the pharmacokinetics of oral semaglutide

<b>Background</b>: Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide. <b>Research design and methods</b>: A single-center, randomized, open-label, parallel-group trial investigated pharmacokinetic interactions of oral semaglutide with omeprazole (40 mg once-daily) in 54 healthy subjects. Primary endpoints were area under the plasma concentration-time curve over 24 h for semaglutide (AUC_{0−24h,semaglutide,Day10}) and maximum concentration of semaglutide (C_{max,semaglutide,Day10}) at day 10. <b>Results</b>: Exposure of semaglutide appeared to be slightly increased, although not statistically significantly, with oral semaglutide plus omeprazole versus oral semaglutide alone (AUC_{0−24h,semaglutide,Day10} [estimated treatment ratio 1.13; 90%CI 0.88, 1.45] and C_{max,semaglutide,Day10} [estimated treatment ratio 1.16; 90%CI 0.90, 1.49]). Gastric pH was higher with oral semaglutide and omeprazole versus oral semaglutide alone. Adverse events were mild or moderate and, most commonly, gastrointestinal disorders. <b>Conclusions</b>: There was a slight non-statistically significant increase in semaglutide exposure when oral semaglutide was administered with omeprazole, but this is not considered clinically relevant and no dose adjustment is likely to be required.

**背景**：首个口服胰高血糖素样肽-1（glucagon-like peptide-1）类似物为司美格鲁肽（semaglutide）与吸收促进剂N-(8-[2-羟基苯甲酰基]氨基)辛酸钠的复方制剂，该促进剂可诱导胃pH值出现一过性局部升高。本研究旨在探讨质子泵抑制剂（proton pump inhibitor）是否会影响口服司美格鲁肽的药代动力学。**研究设计与方法**：本研究为单中心、随机、开放标签、平行组试验，纳入54名健康受试者，考察口服司美格鲁肽与奥美拉唑（omeprazole，40mg，每日一次）的药代动力学相互作用。主要终点为第10天时司美格鲁肽的24小时血浆浓度-时间曲线下面积（AUC_{0−24h,司美格鲁肽,第10天}）与司美格鲁肽的峰浓度（C_{max,司美格鲁肽,第10天}）。**结果**：与单用口服司美格鲁肽相比，联用奥美拉唑的口服司美格鲁肽组的司美格鲁肽暴露量略有升高，但无统计学显著性差异（AUC_{0−24h,司美格鲁肽,第10天}的估计治疗比为1.13；90%置信区间[0.88, 1.45]，C_{max,司美格鲁肽,第10天}的估计治疗比为1.16；90%置信区间[0.90, 1.49]）。联用口服司美格鲁肽与奥美拉唑组的胃pH值高于单用口服司美格鲁肽组。不良事件多为轻度或中度，最常见的为胃肠道不良反应。**结论**：当口服司美格鲁肽与奥美拉唑联用时，司美格鲁肽的暴露量存在轻微且无统计学显著性的升高，但该变化不被认为具有临床相关性，大概率无需调整给药剂量。