{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:12:31Z","timestamp":1790820751014,"version":"4.1.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:00:00Z","timestamp":1718236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Tivozanib, a vascular endothelial growth factor tyrosine kinase inhibitor, has demonstrated efficacy in a phase III clinical trials for the treatment of renal cell carcinoma. However, comprehensive evaluation of its long-term safety profile in a large sample population remains elusive. The current study assessed Tivozanib-related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System FDA Adverse Event Reporting System.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Disproportionality analyses, utilizing reporting odds ratio proportional reporting ratio Bayesian confidence propagation neural network and multi-item gamma Poisson shrinker (MGPS) algorithms, were conducted to quantify signals of Tivozanib-related AEs. Weibull distribution was used to predict the varying risk incidence of AEs over time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Out of 5,361,420 reports collected from the FAERS database, 1,366 reports of Tivozanib-associated AEs were identified. A total of 94 significant disproportionality preferred terms (PTs) conforming to the four algorithms simultaneously were retained. The most common AEs included fatigue, diarrhea, nausea, blood pressure increased, decreased appetite, and dysphonia, consistent with prior specifications and clinical trials. Unexpected significant AEs such as dyspnea, constipation, pain in extremity, stomatitis, and palmar-plantar erythrodysaesthesia syndrome was observed. The median onset time of Tivozanib-related AEs was 37 days (interquartile range [IQR] 11.75\u201391 days), with a majority (n = 127, 46.35%) occurring within the initial month following Tivozanib initiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our observations align with clinical assertions regarding Tivozanib\u2019s safety profile. Additionally, we unveil potential novel and unexpected AE signatures associated with Tivozanib administration, highlighting the imperative for prospective clinical studies to validate these findings and elucidate their causal relationships. These results furnish valuable evidence to steer future clinical inquiries aimed at elucidating the safety profile of Tivozanib.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1408135","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T04:47:55Z","timestamp":1718254075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["A real-world disproportionality analysis of Tivozanib data mining of the public version of FDA adverse event reporting system"],"prefix":"10.3389","volume":"15","author":[{"given":"Kaixuan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"295","DOI":"10.3390\/ph16020295","article-title":"Mechanism underlying triple VEGFR inhibitor tivozanib-induced hypertension in mice model","volume":"16","author":"Alanazi","year":"2023","journal-title":"Pharm. (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.annonc.2020.09.021","article-title":"TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma","volume":"32","author":"Albiges","year":"2021","journal-title":"Ann. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1093\/oncolo\/oyad348","article-title":"Long-term survival in patients with relapsed\/refractory advanced renal cell carcinoma treated with tivozanib: analysis of the phase III TIVO-3 trial","volume":"29","author":"Beckermann","year":"2024","journal-title":"Oncologist"},{"key":"B4","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1093\/ecco-jcc\/jjy216","article-title":"Systematic review and network meta-analysis of medical therapies to prevent recurrence of post-operative crohn\u2019s disease","volume":"13","author":"Burr","year":"2019","journal-title":"J. Crohn\u2019s colitis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1053\/gast.1997.v113.pm9352848","article-title":"Mesalamine in the maintenance treatment of Crohn\u2019s disease: a meta-analysis adjusted for confounding variables","volume":"113","author":"Camm\u00e0","year":"1997","journal-title":"Gastroenterology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1158\/1078-0432.CCR-20-2275","article-title":"FDA approval summary: enfortumab vedotin for locally advanced or metastatic urothelial carcinoma","volume":"28","author":"Chang","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1097\/JCMA.0000000000001026","article-title":"Major adverse cardiovascular events of vascular endothelial growth factor tyrosine kinase inhibitors among patients with different malignancy: a systemic review and network meta-analysis","volume":"87","author":"Chen","year":"2024","journal-title":"J. Chin. Med. Assoc."},{"key":"B8","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/S1470-2045(16)30107-3","article-title":"Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial","volume":"17","author":"Choueiri","year":"2016","journal-title":"Lancet Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1038\/s41591-020-1093-z","article-title":"Targeting the HIF2-VEGF axis in renal cell carcinoma","volume":"26","author":"Choueiri","year":"2020","journal-title":"Nat. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1111\/j.1572-0241.2000.01940.x","article-title":"A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis","volume":"95","author":"Cohen","year":"2000","journal-title":"Am. J. gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"519","DOI":"10.2147\/DDDT.S31442","article-title":"Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma","volume":"7","author":"Cowey","year":"2013","journal-title":"Drug Des. Devel Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1259908","DOI":"10.3389\/fphar.2023.1259908","article-title":"A pharmacovigilance study of etoposide in the FDA adverse event reporting system (FAERS) database, what does the real world say?","volume":"14","author":"Cui","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"20601","DOI":"10.1038\/s41598-022-23726-4","article-title":"A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for niraparib","volume":"12","author":"Guo","year":"2022","journal-title":"Sci. Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2915","DOI":"10.1517\/14656566.2011.636032","article-title":"Progress and contrasts of the development of tivozanib for therapy of kidney cancer","volume":"12","author":"Gupta","year":"2011","journal-title":"Expert Opin. Pharmacother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2217\/fon.12.167","article-title":"Structure, development, preclinical and clinical efficacy of tivozanib (KRN-951, AV-951)","volume":"9","author":"Haberkorn","year":"2013","journal-title":"Future Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"9633048","DOI":"10.1155\/2022\/9633048","article-title":"Five-flavor Sophora flavescens enteric-coated capsules for ulcerative colitis: a systematic review and meta-analysis of randomized clinical trials","volume":"2022","author":"Hou","year":"2022","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"17009","DOI":"10.1038\/nrdp.2017.9","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.2217\/fon-2020-0443","article-title":"Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma","volume":"16","author":"Jacob","year":"2020","journal-title":"Future Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"oyae037","DOI":"10.1093\/oncolo\/oyae037","article-title":"Efficacy, safety, and tolerability of tivozanib in heavily pretreated patients with advanced clear cell renal cell carcinoma","author":"Johns","year":"2024","journal-title":"Oncologist"},{"key":"B20","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41581-020-00359-2","article-title":"Clear cell renal cell carcinoma ontogeny and mechanisms of lethality","volume":"17","author":"Jonasch","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1186\/s12876-021-01887-2","article-title":"Supplemental bifid triple viable capsule treatment improves inflammatory response and T cell frequency in ulcerative colitis patients","volume":"21","author":"Li","year":"2021","journal-title":"BMC Gastroenterol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2165\/00002018-200023060-00004","article-title":"A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database","volume":"23","author":"Lindquist","year":"2000","journal-title":"Drug Saf."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e000853","DOI":"10.1136\/bmjgast-2021-000853","article-title":"Modelling the benefits of an optimised treatment strategy for 5-ASA in mild-to-moderate ulcerative colitis","volume":"9","author":"Louis","year":"2022","journal-title":"BMJ Open Gastroenterol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1080\/14712598.2021.1948529","article-title":"The impact of anti-TNF\u03b1 agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database","volume":"21","author":"Mazhar","year":"2021","journal-title":"Expert Opin. Biol. Ther."},{"key":"B25","first-page":"455","article-title":"Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis","volume":"59","author":"Melincovici","year":"2018","journal-title":"Rom. J. Morphol. Embryol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1111\/apt.13190","article-title":"Systematic review with network meta-analysis: comparative efficacy and safety of budesonide and mesalazine (mesalamine) for Crohn\u2019s disease","volume":"41","author":"Moja","year":"2015","journal-title":"Alimentary Pharmacol. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1016\/S1470-2045(15)00290-9","article-title":"Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial","volume":"16","author":"Motzer","year":"","journal-title":"Lancet Oncol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1200\/JCO.2014.59.0703","article-title":"Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial","volume":"33","author":"Motzer","year":"","journal-title":"J. Clin. Oncol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1038\/ajg.2012.198","article-title":"5-aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease: a meta-analysis of non-referral populations","volume":"107","author":"Nguyen","year":"2012","journal-title":"Am. J. gastroenterology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"562","DOI":"10.2174\/1871520622666220617103126","article-title":"Tivozanib: a new hope for treating renal cell carcinoma","volume":"23","author":"Passi","year":"2023","journal-title":"Anticancer Agents Med. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s11739-019-02253-7","article-title":"Intravitreal anti-VEGF agents and cardiovascular risk","volume":"15","author":"Porta","year":"2020","journal-title":"Intern Emerg. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1007\/s10620-008-0428-2","article-title":"Comparison of mesalazine and balsalazide in induction and maintenance of remission in patients with ulcerative colitis: a meta-analysis","volume":"54","author":"Rahimi","year":"2009","journal-title":"Dig. Dis. Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S1470-2045(19)30735-1","article-title":"Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study","volume":"21","author":"Rini","year":"2020","journal-title":"Lancet Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"862508","DOI":"10.3389\/fphar.2022.862508","article-title":"Post-marketing safety concerns with secukinumab: a disproportionality analysis of the FDA adverse event reporting system","volume":"13","author":"Shu","year":"","journal-title":"Front. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"789","DOI":"10.2147\/CLEP.S365513","article-title":"A real-world disproportionality analysis of olaparib: data mining of the public version of FDA adverse event reporting system","volume":"14","author":"Shu","year":"","journal-title":"Clin. Epidemiol."},{"key":"B36","first-page":"2116","article-title":"Sulfasalazine and mesalazine for the maintenance therapy of Crohn\u2019s disease: a meta-analysis","volume":"89","author":"Steinhart","year":"1994","journal-title":"Am. J. gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"7051","DOI":"10.1002\/cam4.5504","article-title":"Optimizing targeted drug selection in combination therapy for patients with advanced or metastatic renal cell carcinoma: a systematic review and network meta-analysis of safety","volume":"12","author":"Xie","year":"2023","journal-title":"Cancer Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13045-016-0374-y","article-title":"New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy","volume":"10","author":"Zarrabi","year":"2017","journal-title":"J. Hematol. Oncol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1408135\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T04:47:59Z","timestamp":1718254079000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1408135\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,13]]},"references-count":38,"alternative-id":["10.3389\/fphar.2024.1408135"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1408135","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,13]]},"article-number":"1408135"}}