{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:17:27Z","timestamp":1783585047353,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"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>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Posterior reversible encephalopathy syndrome (PRES) is a rare but potentially severe complication of VEGF-pathway inhibition. A recent FAERS analysis supported PRES as a probable class effect of angiogenesis inhibitors but found no association with continuous VEGFR affinity, did not formally test a categorical VEGFR-2 selectivity contrast, and could not characterise time to onset. Complementing that work, we compared disproportionality signals across 22 VEGFi\/VEGFRi agents and examined whether signal ranking tracked VEGFR-2 selectivity, systemic exposure, and published case-report volume.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this observational pharmacovigilance study we analysed FAERS reports (2010-Q1 to 2026-Q1) via the openFDA API. PRES was ascertained by MedDRA Preferred Terms. Four disproportionality metrics (ROR, PRR, BCPNN-IC with IC025, EBGM) were computed for each agent; robust signals were confirmed by Bonferroni and Benjamini-Hochberg correction. We characterised the drug-start-to-FDA-receipt reporting interval (a reporting-delay measure, not true clinical time-to-onset), explored the correlation between published VEGFR-2 IC50 and log-ROR, and performed a targeted PubMed scan against the case-report literature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Under formal multiplicity correction (Bonferroni and Benjamini-Hochberg), 13 of 16 evaluable agents produced robust elevated PRES signals (ROR up to 16.68). Signal intensity separated cleanly by VEGFR-2 selectivity: every highly selective VEGFR-TKI (tivozanib, lenvatinib, fruquintinib, axitinib; ROR 9.74\u201316.68) ranked above every multi-kinase agent (ROR 2.00\u20136.05) (Mann-Whitney p = 0.005; Spearman rho = 0.84, p = 0.001). By contrast, the continuous IC50-ROR correlation was non-significant primarily (rho = \u22120.38, p = 0.25) and exclusion-sensitive, hence hypothesis-generating only. Intravitreal anti-VEGF agents produced no positive signal, an internal negative control. Nintedanib yielded an inverse signal (ROR 0.34), likely indication channelling. Tivozanib and ramucirumab (ROR 7.56) were under-represented in the PubMed case-report literature (FAERS-PubMed rho = 0.09, p = 0.78).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PRES disproportionality varied substantially across VEGFi\/VEGFRi agents, with intravitreal agents serving as an internal negative control consistent with a systemic-exposure mechanism. IC50-based analyses were small-sample and hypothesis-generating only. Tivozanib and ramucirumab emerged as under-represented signals meriting confirmation; selective VEGFR-TKI recipients may warrant close blood-pressure monitoring and a low threshold for neuroimaging.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1887454","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T07:44:10Z","timestamp":1783583050000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Posterior reversible encephalopathy syndrome across 22 VEGF-pathway inhibitors in the FDA adverse event reporting system: reporting patterns and reporting-interval characteristics"],"prefix":"10.3389","volume":"17","author":[{"given":"Ji","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology, Lu\u2019an People\u2019s Hospital (The Affiliated Lu\u2019an Hospital of Anhui Medical University)","place":["Lu\u2019an, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Lu\u2019an People\u2019s Hospital (The Affiliated Lu\u2019an Hospital of Anhui Medical University)","place":["Lu\u2019an, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhou","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Lu\u2019an People\u2019s Hospital (The Affiliated Lu\u2019an Hospital of Anhui Medical University)","place":["Lu\u2019an, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1007\/s00415-022-11450-y","article-title":"Drugs associated with posterior reversible encephalopathy syndrome, a worldwide signal detection study","volume":"270","author":"Balcerac","year":"2023","journal-title":"J. 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