Assessment of acute kidney injury related to small-molecule protein kinase inhibitors using the FDA adverse event report
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ORIGINAL ARTICLE
Assessment of acute kidney injury related to small‑molecule protein kinase inhibitors using the FDA adverse event reporting system Qianqian Fan1 · Jie Ma2 · Bo Zhang1 · Qiuyue Li1 · Fang Liu1 · Bin Zhao1 Received: 31 May 2020 / Accepted: 17 September 2020 / Published online: 1 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Small-molecule protein kinase inhibitors (PKIs) have substantially improved clinical outcomes of various diseases. However, some studies suggested these agents might induce acute kidney injury (AKI). This study was designed to comprehensively assess the adverse events of AKI in real-world patients receiving small-molecule PKIs using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods The FAERS data between 2004 and 2019 were extracted to describe the characteristics of AKI cases after the use of small-molecule PKIs approved by the FDA. The reporting odds ratio (ROR) with 95% confidence interval (CI) for AKI was calculated for each small-molecule PKI agent. A disproportionality signal was defined when the lower limit of 95% CI > 1. Results Among the 462,020 adverse event reports for small-molecule PKIs, 9970 (2.16%) were identified as AKI cases. The median AKI onset time was 32 (interquartile range 11–124) days after the initiation of small-molecule PKI treatment. A total of 61.38% and 26.04% of AKI cases resulted in hospitalization and death, respectively. Based on RORs, 14 of 52 small-molecule PKIs yielded disproportionality signals for AKI, including six VEGFR inhibitors, three mTOR inhibitors and five small-molecule PKIs with other targets. The agents with the highest AKI RORs were entrectinib (ROR 6.40, 95% CI 2.23, 18.34), sirolimus (ROR 3.76, 95% CI 3.45, 4.09), and cobimetinib (ROR 3.40, 95% CI 2.69, 4.28). Conclusion Analysis of the FAERS data helped identify the small-molecule PKIs that were most frequently reported for AKI. Further investigations are needed to confirm these potential risks. Keywords Small-molecule protein kinase inhibitors · Acute kidney injury · Adverse event · FAERS · Real-world data · Reporting odds ratio
Introduction
Qianqian Fan and Jie Ma contributed equally to this article. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04151-8) contains supplementary material, which is available to authorized users. * Bin Zhao [email protected] 1
Department of Pharmacy, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
Departemnt of Nephrology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
2
The last two decades have witnessed unprecedented success in the development of protein kinase inhibitors (PKIs). As of December 2019, a total of 52 small-molecule PKIs with various targets have been approved by the US Food and Drug Administration (FDA) (Online Resource 1) [1, 2]. These new agents have brought promisi
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