Slimano Florian, Le Bozec Antoine, Cransac Amélie, Foucher Pascal, Lesauvage François, Delclaux Bertrand, Dory Anne, Mennecier Bertrand, Bertrand Benjamin, Gubeno-Dumon Marie-Christine, Dukic Sylvain, Mongaret Céline, Bouché Olivier, Hettler Dominique, Boulin Mathieu, Dewolf Maxime, Kanagaratnam Lukshe
Department of Pharmacy, CHU Reims, Rue Général Koenig, 51100 Reims, Reims, France; Université de Reims Champagne-Ardenne (URCA), Faculty of Pharmacy, 51 rue Cognacq-Jay, 51100 Reims, Reims, France.
Department of Pharmacy, CHU Reims, Rue Général Koenig, 51100 Reims, Reims, France.
Lung Cancer. 2022 Apr;166:114-121. doi: 10.1016/j.lungcan.2022.02.007. Epub 2022 Feb 24.
Pemetrexed is associated with hematological toxicity. Drug-drug interactions (DDIs) between methotrexate and proton pump inhibitors (PPIs) induce a higher risk of hematological toxicity due to the inhibition of methotrexate excretion by PPIs. As pemetrexed and methotrexate are both excreted by human organic anion transporter 3 (hOAT3), this study investigates the hypothetical DDI between pemetrexed and PPIs in lung cancer patients. The primary objective was the occurrence of severe (grade ≥ 3) hematological toxicity. The secondary objectives were to describe the type of hematological toxicity and associated clinical consequences (NCT03537833).
PPI consumption was collected for each patient receiving pemetrexed-based anticancer chemotherapy from May 2018 to October 2020 in a prospective multicentric observational and nonrandomized study. Multivariate Cox regression and propensity score (PS) adjustment, PS matching and inverse weighting on PS (IPTW) methods were used.
PPI consumption (55 among 156 included patients) was associated with a significantly higher risk of severe hematological toxicity in the multivariable Cox regression model (hazard ratio HR = 2.51, 95% confidence interval [1.47-4.26]; p = 0.005). Similar results were found with PS adjustment (HR = 1.91 CI95% [1.14-3.20]; p = 0.002), PS-matching (HR = 1.93 CI95% [1.08-3.45]; p = 0.02) and IPTW method (HR = 2.06 CI95% [1.27-3.35]; p = 0.004). Severe neutropenia and anemia occurred in 32.7% and 14.1% of patients, respectively. This resulted in 48 anticancer chemotherapy postponements and 24 dose adjustments, 26 growth factor prescriptions, 24 red blood cell transfusions, and 20 hospitalizations.
The results strongly suggest an association between PPI consumption and pemetrexed-related severe hematological toxicity. Deprescription of PPIs when feasible should be considered to prevent this DDI.
培美曲塞与血液学毒性相关。甲氨蝶呤与质子泵抑制剂（PPI）之间的药物相互作用（DDI）会因PPI抑制甲氨蝶呤排泄而导致更高的血液学毒性风险。由于培美曲塞和甲氨蝶呤均通过人类有机阴离子转运体3（hOAT3）排泄，本研究调查了肺癌患者中培美曲塞与PPI之间可能存在的DDI。主要目标是发生严重（≥3级）血液学毒性。次要目标是描述血液学毒性的类型及相关临床后果（NCT03537833）。
在一项前瞻性多中心观察性非随机研究中，收集了2018年5月至2020年10月期间接受以培美曲塞为基础的抗癌化疗的每位患者的PPI使用情况。采用多变量Cox回归和倾向评分（PS）调整、PS匹配以及PS逆加权（IPTW）方法。
在多变量Cox回归模型中，PPI使用情况（156例纳入患者中有55例）与严重血液学毒性风险显著升高相关（风险比HR = 2.51，95%置信区间[1.47 - 4.26]；p = 0.005）。PS调整（HR = 1.91，95%CI[1.14 - 3.20]；p = 0.002）、PS匹配（HR = 1.93，95%CI[1.08 - 3.45]；p = 0.02）和IPTW方法（HR = 2.06，95%CI[1.27 - 3.35]；p = 0.004）也得到了类似结果。分别有32.7%和14.1%的患者发生严重中性粒细胞减少和贫血。这导致48次抗癌化疗推迟、24次剂量调整、26次生长因子处方、24次红细胞输血以及20次住院治疗。
结果强烈提示PPI使用与培美曲塞相关的严重血液学毒性之间存在关联。应考虑在可行时停用PPI以预防这种DDI。
