Detrimental impact of gastric acid suppressants on vascular endothelial growth factor receptor tyrosine kinase inhibitors efficacy: evidence from a systematic review and meta-analysis.
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Abstract
Background: This meta-analysis evaluated the prevalence of gastric acid suppressants (GASs) in patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and explored drug-drug interactions (DDIs).
Methods: PubMed, Embase, and Cochrane Library were searched upto 20 October 2024. Studies comparing VEGFR-TKIs monotherapy versus VEGFR-TKIs with GASs, reporting pharmacodynamic (PD), pharmacokinetic (PK), or adverse events (AEs), were analyzed using random-effects models. Subgroups included cancer types and VEGFR-TKI types.
Results: 24 studies comprising 6,406 patients were included. The prevalence of GASs use in VEGFR-TKIs users was 40% (95% CI 31-50%). GASs significantly impaired survival, increasing mortality risk by 29% (OS HR 1.29,95% CI 1.14-1.45) and progression risk by 31% (PFS HR 1.31, 95% CI 1.06-1.61). PK analyses revealed clinically meaningful exposure reductions (AUC0-24GMR 0.78, 90% CI 0.65-0.94; Cmax GMR 0.80, 90% CI 0.70-0.91). AE incidence (except vomiting) did not differ between groups.
Conclusion: GASs may reduce the efficacy of most types of VEGFR-TKIs by decreasing their bioavailability, thereby having a detrimental effect on patient survival outcomes. It is recommended to give priority to H2 receptor antagonists (H2RAs) and monitor blood drug concentrations to optimize efficacy.
背景：本荟萃分析评估了在接受血管内皮生长因子受体酪氨酸激酶抑制剂（VEGFR-TKIs）治疗的患者中胃酸抑制剂（GASs）的患病率，并探讨了药物-药物相互作用（ddi）。方法：检索截止到2024年10月20日的PubMed、Embase和Cochrane Library。比较VEGFR-TKIs单药治疗与VEGFR-TKIs联合GASs的研究，报告药效学（PD）、药代动力学（PK）或不良事件（ae），使用随机效应模型进行分析。亚组包括癌症类型和VEGFR-TKI类型。结果：纳入24项研究，6406例患者。在VEGFR-TKIs使用者中，GASs的使用率为40% （95% CI 31-50%）。GASs显著损害了生存，使死亡风险增加29% (OS HR 1.29,95% CI 1.14-1.45)，使进展风险增加31% （PFS HR 1.31, 95% CI 1.06-1.61）。PK分析显示有临床意义的暴露减少(AUC0-24GMR 0.78, 90% CI 0.65-0.94；Cmax GMR 0.80, 90% CI 0.70-0.91)。AE发生率（呕吐除外）各组间无差异。结论：GASs可能通过降低大多数类型的VEGFR-TKIs的生物利用度来降低其疗效，从而对患者的生存结果产生不利影响。建议优先使用H2受体拮抗剂（H2RAs），并监测血药浓度以优化疗效。协议注册：www.crd.york.ac.uk/prospero标识符CRD42024597729。
期刊介绍：
Advances in drug development technologies are yielding innovative new therapies, from potentially lifesaving medicines to lifestyle products. In recent years, however, the cost of developing new drugs has soared, and concerns over drug resistance and pharmacoeconomics have come to the fore. Adverse reactions experienced at the clinical trial level serve as a constant reminder of the importance of rigorous safety and toxicity testing. Furthermore the advent of pharmacogenomics and ‘individualized’ approaches to therapy will demand a fresh approach to drug evaluation and healthcare delivery.
Clinical Pharmacology provides an essential role in integrating the expertise of all of the specialists and players who are active in meeting such challenges in modern biomedical practice.
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