van Doorn Leni, Heersche Niels, de Man Femke M, de Bruijn Peter, Bijl Ivo, Oomen-de Hoop Esther, Eskens Ferry A L M, van der Gaast Ate, Mathijssen Ron H J, Bins Sander
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Clin Pharmacol Ther. 2022 Feb;111(2):455-460. doi: 10.1002/cpt.2444. Epub 2021 Oct 31.
Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC ) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC of capecitabine (95% confidence interval (CI) -10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI -16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.
回顾性数据表明，质子泵抑制剂（PPI）降低胃酸会损害卡培他滨的溶解及随后的吸收，从而可能减少卡培他滨的暴露量。因此，我们前瞻性地研究了埃索美拉唑对卡培他滨药代动力学的影响。在这项随机交叉研究中，癌症患者被分为2个序列组，每组包括3个阶段：在服用卡培他滨前3小时给予埃索美拉唑（A阶段）、单独服用卡培他滨（B阶段），以及在服用卡培他滨前3小时同时给予可乐和埃索美拉唑（C阶段）。主要终点是通过血浆浓度-时间曲线从零至无穷大的面积（AUC）评估的卡培他滨暴露量的相对差异（RD），并采用线性混合效应模型进行分析。22例可评估患者纳入分析。服用埃索美拉唑后，卡培他滨的AUC增加了18.9%（95%置信区间（CI）为-10.0%至57.0%，P = 0.36）。此外，服用埃索美拉唑后卡培他滨的半衰期显著延长（中位数0.63小时对0.46小时，P = 0.005）。同时服用可乐并未完全逆转服用埃索美拉唑后观察到的效应（RD 3.3%（95%CI -16.3至27.4%，P = 1.00）。卡培他滨暴露不受埃索美拉唑联合治疗的负面影响。因此，卡培他滨药代动力学的改变并不能解释PPI联合治疗的癌症患者假定的更差临床结局。
