Meta Analysis Of Proton Pump Inhibitors Delayed High Dose Methotrexate Elimination

Objective:To assess the association between co-administration of proton pump inhibitor(PPIs)with plasma MTX concentration and delayed MTX elimination.Methods:We searched PubMed,the Cochrane Database,Embase,WHO International Clinical Trials Registry Platform,Wan fang,Chinese National Knowledge Infrastructure,VIP database and Chinese Biomedical Literature Database,for randomized controlled trials(RCT)or retrospective cohort and case-control studies about MTX co-administration with PPIs for tumor chemotherapy.The English search terms are as follow:(methotrexate OR MTX)AND(proton pump inhibitors OR PPIs OR PPI);Chinese search terms are:methotrexate,proton pump inhibitor.Quality of the included studies was evaluated according to Cochrane Handbook evaluation tool and the Newcastle Ottawa Scale(NOS),and performed the Meta analysis by RevMan statistical software(version 5.3).Results:10 retrospective cohort studies were included in the Meta analysis,with a total of 2760 cycles of high dose MTX treatment.The result of Meta analysis showed compared with patients who didn't receive PPIs,patients who received PPIs had a significant increase in plasma concentration 24 h after MTX infusion,the difference was statistically significant(MD 2.71,95%CI 0.55-4.87,p<0.05).The plasma concentration was significantly at 48 h after MTX infusion,and difference was statistically significant(MD 0.14,95%CI 0.06?0.22,p<0.05).Furthermore,delayed MTX elimination was more frequent in patients receiving PPIs,and the difference was statistically significant(RR 1.72,95%Cl 1.20-2.48,p=0.003).Conclusion:This Meta analysis indicates that co-administration with PPIs increased plasma concentrations at 24 h and 48 h after MTX infusion and delayed MTX elimination.Therefore,in the process of using high-dose MTX anti-tumor therapy,besides routine use of hydration,alkalized urine,calcium leucovorin rescue and TDM monitoring,it is also necessary to pay attention to the drug interactions such as PPIs,avoid using drugs which interact with MTX as soon as possible,so as to reduce and prevent the occurrence of MTX-related adverse reactions,ultimately achieve the goal of safe drug using high-dose MTX.However,due to the fact that all of the included studies are retrospective,as well as the presence of significant heterogeneity,higher quality clinical studies are warranted in order to confirm these findings.