A real-world pharmacovigilance study of brentuximab vedotin based on the FAERS database from 2011 to 2024

A real-world pharmacovigilance study of brentuximab vedotin based on the FAERS database from 2011 to 2024 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A real-world pharmacovigilance study of brentuximab vedotin based on the FAERS database from 2011 to 2024 Huan Sun, Qiaoli Zhai, Yuan Li, Kourong Shi, Wei Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6876929/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) that targets CD30 and is primarily used in the treatment of CD30-positive lymphoma. While BV has shown success in treating patients with this type of lymphoma, there have been reports of serious adverse drug events (ADEs) associated with its use. This study aims to investigate the ADEs related to BV reported in the FDA Adverse Event Reporting System (FAERS) database from the third quarter of 2011 (Q3 2011) to the second quarter of 2024 (Q2 2024). Furthermore, the possibility and potential targets of peripheral neuropathy and acute kidney injury (AKI) caused by BV were analyzed. Targets associated with occurrence of ADEs were obtained by applying GeneCards database and key genes were enriched by GO and KEGG methods. A total of 6,515 adverse event reports and 21,055 ADEs related to BV were retrieved, half of which occurred within 21 days after first medication. The most frequently preferred terms (PTs) included peripheral sensory neuropathy, pneumocystis jirovecii pneumonia, and febrile neutropenia. The analysis of FAERS data allows for a thorough understanding of the real-world use of BV and helps to proper utilize and manage these potential adverse events. brentuximab vedotin FAERS pharmacoviligilance network pharmacology peripheral neurophthy acute kidney injury pneumonia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1. Introduction The Food and Drug Administration (FDA) officially granted approval for the first ADC drug—Gemtuzumab ozogamicin in 2000. However, the drug was withdrawn from the market in 2010 due to severe side effects and later re-approved in 2017[1]. BV received FDA approval in 2011 and was introduced to the Chinese market in 2020. With a wealth of clinical experience accumulated since its introduction, BV has been designated as a standard treatment option by the National Comprehensive Cancer Network (NCCN). Notably, BV marks the first FDA-approved drug for the treatment of systemic anaplastic large cell lymphoma (sALCL) and classical Hodgkin lymphoma (cHL) in the past 45 years[2] . BV is formulated with a monoclonal antibody designed to target CD30, coupled with monomethyl auristatin E (MMAE), a potent microtubule inhibitor[3] . As an ADC, BV possesses the ability to specifically identify and bind to cancer cells' surfaces. Once absorbed by these malignant cells, the linker molecule MMAE is triggered to release the drug in targeted circumstances, ultimately leading to the destruction of cancer cells [4]. BV exhibits a prolonged circulation time within the bloodstream, effectively targeting and eradicating tumor cells expressing CD30. Leveraging its precise targeting mechanism on cancer cells, BV offers the advantages of minimized side effects and superior therapeutic efficacy compared to traditional chemotherapy agents. However, there have been some ADEs during the application of BV. The relatively common ADEs are peripheral neuropathy and neutropenia. In addition, there have been numerous reports of hematotoxicity and neurotoxicity linked to the use of ADCs, and these effects may be related to the cytotoxic payload linker MMAE[5]. The mechanisms underlying these ADEs may be tied to off-target effects of non-tumor cells, targeted antigens uptake of non-tumor cells or non-target antigens uptake of non-tumor cells [6]. It is also worth noting that MMAE has to been shown to be nephrotoxicity [7]. ADCs like Disitamab vedotin explicitly warn about renal-related ADEs in their instructions, including the development of proteinuria, hematuria, and renal dysfunction. These renal ADEs might be attributed to the hepatic and renal metabolism of the conjugates[8]. In a Phase III trial involving patients with cHLs who had undergone autologous hematopoietic stem cell transplantation, it was found that 67% of patients experienced varying degrees of peripheral neuropathy following treatment with BV [9]. Peripheral neuropathy is one of the main reasons for the withdrawal of BV, including peripheral sensory neuropathy and peripheral motor neuropathy, which is caused by brain and peripheral nerve injury[10-11]. It often manifested as weakness, numbness and pain in the hands and feet, and may also impact other bodily functions like digestion and urination [12]. It may be linked to an increase in inflammatory factors and a decrease in peripheral nerve growth factors [13]. When sensory nerves are affected, individuals may experience limb hypoesthesia or paresthesia, which can persist long after the offending medication has been discontinued [14]. Acute Kidney Injury (AKI) is a condition characterized by a sudden and rapid decline in renal function over a period of 1-7 days, lasting for more than 24 hours. Symptoms of AKI often include decreased urine output and swelling, among others. Common causes of AKI include insufficient renal blood flow, exposure to toxic substances that damage the kidneys, and kidney infections [15]. The onset of AKI is swift and can lead to complications such as pleural effusion and muscle weakness [16]. Research has shown that individuals with pre-existing chronic kidney disease are at a higher risk of developing AKI compared to those with healthy kidneys. Chronic kidney disease is identified as a significant risk factor for the development of AKI [17]. FAERS is a database that plays a crucial role in the collection and analysis of ADEs associated with marketed drugs. It encompasses a wealth of information on ADEs, drug abuse, misuse, and more, serving as a vital tool for monitoring drug safety and providing guidance for the rational use of drugs clinically [18]. However, current studies on ADEs of BV may not be in-depth enough. The study seeks to address this gap by conducting a comprehensive analysis of the connections between BV and its associated ADEs. In addition to this, the study focuses on two specific ADEs: peripheral neuropathy, a commonly observed side effect, and acute kidney injury (AKI), a newly reported ADE. By examining the underlying targets and pathways related to these ADEs, the research aims to provide insights that can guide the rational use of BV and improve patient outcomes in the future. 2. Materials and Methods 2.1 Data sources and processing The data used in this research was sourced from the American Standard Code for Information Interchange Ⅱ (ASCⅡ) , retrieved from the FAERS database spanning from Q1 2004 to Q2 2024. The collected data was then transferred into SAS 9.4 software for thorough analysis and interpretation. ADE reports were screened by searching “DRUGNAME--- Brentuximab vedotin” as the primary suspect drug. The duplicate reports were removed following the guidelines provided by the U.S. FDA[19]. Since BV was first marketed in 2011, the study focused on data obtained from the FAERS database, specifically from Q3 2011 to Q2 2024, 2.2 Application of MedDRA The latest version of the Medical Dictionary for Regulatory Activities (MedDRA 27.0) was utilized to encode the ADEs listed in the FAERS database. The names of PTs were also revised and recalibrated. The SOCs and PTs served as the criteria for assessing and analyzing the data further. 2.3 Data analysis The research utilized a case-non-case analysis method to identify potential signals of ADEs. A 2×2 contingency table was presented for disproportionality analysis (Table 1 ). Several algorithms, including ROR, PRR, BCPNN, and MGPS, are commonly utilized for detecting signals of ADEs[20]. These algorithms are employed to quantify the strength of the relationship between BV and various ADEs, demonstrating a level of credibility. Of these algorithms, ROR is particularly prominent and is frequently utilized in signal detection (Table 2). 2.4 Target acquisition and Pathway Analysis for Peripheral Neuropathy, Acute Kidney Injury (AKI), and Pneumonia GeneCards database (https://www.genecards.org/) was retrieved to obtain disease-related targets by searching the key terms “Peripheral neuropathy”,“Acute kidney injury”, and “Penumonia” respectively. All targets obtained were integrated in an excel spreadsheet, with any duplicate genes removed to ensure accuracy of the data. And finally key genes were obtained through the correction of the Uniprot database. Subsequently, the information on the key genes was inputted into the DAVID database (https://david.ncifcrf.gov/summary.jsp), with the settings adjusted to focus on "OFFICIAL_GENE_SYMBOL" for Homo sapiens. The Gene Ontology (GO) tool was employed to provide insights into the functions of the key proteins in terms of biological processes (BP), cellular components (CC), and molecular functions (MF). Additionally, KEGG pathway enrichment analysis was utilized to identify pathways that are linked to the diseases of interest. 3. Results 3.1 Total ADE reports among BV users in the FAERS database from Q3 2011 to Q2 2024 In the study, ADE reports ( n =6,515) and ADEs related to BV ( n =21,055) were finally obtained from the FAERS database between Q3 2011 and Q2 2024 (Figure 1). It was observed that half of the ADE reports occurred within 21 days after the first medication of BV. Furthermore, the ADE reports continued for up to a year following the initial medication (Figure 2A). And ADE reports accounted for a relatively high proportion within 30 days after first medication of BV ( n =1,577, 59.95%) (Figure 2B). These findings highlight the importance of patient vigilance and prompt communication between patients and healthcare providers in cases of discomfort, particularly in the early stages of BV treatment. 3.2 Demographic characteristic analysis of ADE reports Excluding reports that were unclear or lacked sufficient detail, it was found that a higher proportion of male patients ( n =2,729, 41.89%) experienced adverse events compared to female patients. Additionally, patients between the ages of 18-44 years were more likely to report adverse events ( n =1,325, 20.34%) than other age groups. Among different occupations, doctors were the most frequent reporters of adverse events ( n =3,406, 52.28%). The data also showed that during 2011 to 2024, the number of adverse events reported in 2020 was significantly higher ( n =823). Furthermore, the severity of ADEs caused by BV appeared to be relatively serious (Figure 3). The study also examined the distribution of target patients in various regions around the world (Figure S2). These findings indicate the importance of closely monitoring patients who are prescribed BV to ensure their safety and well-being. 3.3 The signals of ADEs detected at the SOC level At the SOC level, the most common reported adverse events included general disorders and administration site conditions, infections and infestations, and investigations. These accounted for 13.91%, 10.06%, and 9.79% of the total number of adverse events, respectively (Figure 4). When ranked by the reporting odds ratio (ROR), the top 5 SOCs with the highest ROR values were infections and infestations (20.48%), investigations (15.26%), nervous system disorders (8.43%), respiratory, thoracic and mediastinal disorders (8.03%), and blood and lymphatic system disorders (6.83%) (Table 3 ). 3.4 The signals of ADEs detected at the PT level At the PT level, Pyrexia, Peripheral neuropathy, Febrile neutropenia were observed relatively frequent (Figure 5A ). After excluding PTs unrelated to ADEs such as “Off label use” and then sorted according to ROR values in descending order, the top 5 PTs were peripheral sensory neuropathy, pneumocystis jirovecii pneumonia, febrile neutropenia, myelosuppression, and peripheral neuropathy. It is worthy noted that pancytopenia, leukopenia, sepsis, aspartate aminotransferase increased, alanine aminotransferase increased, pleural, and effusion were not mentioned in the instruction (Table 4 ). A forest plot diagram was utilized in order to represent the differences betweenvarious ADEs more intuitively (Figure 5B ) . Additionally, a Venn diagram illustrating PT overlaps calculated by four pharmacovigilance algorithms was provided (Figure 5C ). More detailed information regarding ADE signal strength at the PT level was shown in the supplementary material (Table S1). 3.5 Signal detection of serious ADE reports Consistent with the genral trend of ADE reports, 50% of all reports for serous ADEs occurred within 21 days of starting BV medication (Figure 6A ). A significant proportion of serious ADE reports ( n =1,524, 56.63%) were reported within 30 days of starting BV medication (Figure 6B ) . After excluding any reports that lacked clarity, it was found that the percentage of male patients ( n =2,523, 43.15%) was higher than that of female patients. Addtionally, the proportion of patients aged 18-44 years old was higher ( n =1,278, 21.78%) than other age groups.Among individuals from different occupations, doctors reported the highest number of serious adverse events( n =3,192, 54.4%). During 2011-2024, the number of serious adverse events reported in 2020 was higher ( n =764) (Figure 7). At the SOC level, sorted according to ROR values in descending order, the top 5 serious SOCs were infections and infestations (20.81%), investigations (14.45%), nervous system disorders (9.25%), blood and lymphatic system disorders (7.51%) , and respiratory,thoracic and mediastinal disorders (7.51%) (Table 5 ). Similarly, at the PT level, the top 5 serious PTs were pyrexia, febrile neutropenia, peripheral neuropathy, neutropenia, and white blood cell count decreased (Table 6 ). The table illustrating the signal strength of serious ADEs at the PT level was shown in the supplementary material (Table S2). These findings emphasize the importance of monitoring and paying close attention to patients experiencing the aforementioned serious ADEs while they are being treated with the medication of BV. 3.6 Analysis of potential targets and pathways of peripheral neropathy and AKI caused by BV A comprehensive analysis of peripheral neuropathy-related targets revealed a total of 1262 GO items. Within the BP category, there were 938 items identified, with a focus on positive regulation of gene expression, signal transduction, and negative regulation of the apoptotic process. In terms of CC category, 171 items were identified, with a predominant presence in the cytosol, cytoplasm, and plasma membrane. The MF category encompassed 153 items, with a strong emphasis on protein binding, identical protein binding, and ATP binding (Figure 8A). Subsequently, pathway analysis was conducted by using the database, a total of 209 pathways were enriched and 176 related pathways were screened according to P < 0.01, among which the top 5 pathways were pathways of neurodegeneration - multiple diseases, AGE-RAGE signaling pathway in diabetic complications, amyotrophic lateral sclerosis, PI3K-Akt signaling pathway, and HIF-1 signaling pathway (Figure 8B). In the analysis of AKI-related targets, a total of 1,492 GO items were screened. Within the Biological Process (BP) category, there were 1,198 specific items identified. These items predominantly revolved around the topics of positive regulation of gene expression, signal transduction, and negative regulation of apoptosis.The CC category included 142 items, which mainly involed ctosol,cytoplasm,and nucleus. The MF category included 152 items, which mainly involved identical protein binding, metal ion bingding, and ATP binding (Figure 8C). Subsequently, this database was utilized for pathway analysis, resulting in a total of 191 pathways being enriched. Among these, 162 pathways were identified as being significantly related based on a significance level of P < 0.01. The top 5 pathways identified were the PI3K-Akt signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, JAK-STAT signaling pathway, and endocrine resistance(Figure 8D). 4. Discussion In this study, the analysis of ADEs associated with the use of BV revealed several noteworthy ADEs that were not specifically mentioned in the product instructions, such as leukopenia (ROR 5.12, PRR 5.10, IC 2.35, 95% EBGM 5.09), sepsis (ROR 4.83, PRR 4.80, IC 2.62, 95% EBGM 4.79), aspartate aminotransferase increased (ROR 3.99, PRR 3.98, IC 1.99, 95% EBGM 3.98), alanine aminotransferase increased (ROR 3.69, PRR 3.68, IC 1.88, 95% EBGM 3.68), and pleural effusion (ROR 3.58, PRR 3.57, IC 1.83, 95% EBGM 3.56) . In addition, 82 cases of tachycadia related to BV administration were reported in FAERS database. Previous studies have found that microtubule inhibotors can cause cardiac toxicity, including myocardial infarction, heart failure, and arrhythmia[21-22].Therefore, the occurrence of tachycardia in patients treated with BV may be attributed to the pharmacological properties of MMAE. In addition to tachycardia, the FAERS database also documented 248 cases of pneumonia associated with BV. A recent case report described a 40-year-old woman with cutaneous T-cell lymphoma who developed pneumonia and diffuse alveolar injury following BV treatment[23]. The issue of drug-related pneumonia is a significant concern, characterized by inflammatory reactions in the lungs triggered by drugs and their metabolites through direct cytotoxic effects or allergic reactions. Alongside brentuximab vedotin, several chemotherapy agents such as bleomycin, cyclophosphamide, vinblastine, and etoposide have been implicated in causing drug-related pneumonia [24-25]. Chemotherapy-induced pneumonia can be attributed to various factors. Firstly, chemotherapy often compromises immune function, rendering patients more susceptible to infections. Secondly, frequent hospital visits and prolonged hospital stays further increase the risk of pneumonia acquisition. Additionally, chemotherapy-induced pneumonia can be linked to factors such as neutropenia, mucosal damage, and structural alterations in the lungs [26-27]. Beyond chemotherapeutic agents, certain antibiotics like amikacin have also been associated with the development of pneumonia post-administration[28]. Currently, there is a growing number of research on peripheral neuropathy caused by the use of BV [29-31] . Commonly prescribed drugs for treating peripheral neuropathy resulting from chemotherapy include duloxetine, pregabalin, and opiums[32]. However, these drugs still have some side effects. For instance, duloxetine, primarily used to treat depression, has been found to alleviate neuralgia; however, it can lead to adverse effects such as increased blood pressure, insomnia, headaches, and dysuria [33]. Similarly, long-term use of pregabalin and opioids can potentially result in addiction. A concerning finding from the FAERS database revealed 110 reported cases of AKI associated with BV use. Strikingly, AKI was not listed in the prescribing information for BV, highlighting it as a newly identified ADE. In 2024, a case was reported detailing a 73-year-old man with a medical history of hypertension, chronic kidney disease, and benign prostatic hyperplasia who experienced AKI following BV treatment for mycosis fungoides [34]. A study found that CD30-deficient mice exhibited reduced inflammation in a kidney injury model compared to normal mice[35]. Additionally, research has indicated that CD4 + cells play a role in the pathogenesis of AKI, with a connection observed between CD30 and CD4 + [36-37]. Therefore, the development of AKI due to BV may involve the regulatory influence of CD30 on CD4 + cells[38-40]. It is important to note that many chemotherapy drugs are eliminated through the kidneys, emphasizing the need for caution in patients with renal impairment following BV administration. In conclusion, further research is warranted to elucidate the relationships and potential mechanisms linking BV to AKI. There are certain limitations associated with the FAERS, a database comprised of ADEs reported artificially. Some of these limitations include incomplete reporting information, inaccuracies in reporting formats, and redundant reports [41]. For instance, there have been instances of inaccurate reporting, such as the confusion between peripheral neuropathy and peripheral sensory neuropathy. Despite these limitations, BioVeris (BV) stands out for its long history of clinical use, wide therapeutic ranges, and effectiveness in treatment. It proves challenging to develop alternative drugs with fewer ADEs compared to BV. Although Antibody-Drug Conjugates (ADCs) are still under ongoing research, there are measures that can be implemented to reduce toxicity. These include the use of small molecule drugs with different mechanisms of action and the enhancement of drug delivery uniformity and pharmacokinetic characteristics through the application of site-specific coupling technologies[42-43]. 5. Conclusion The study focused on collecting and analyzing ADEs of BV in the FAERS database from Q3 2011 to Q2 2024.The findings of this study emphasize the importance for clinicians and clinical pharmacists to closely monitor both common and newly emerging ADEs linked to BV use. Of particular concern is the relatively high incidence rate of peripheral neuropathy attributed to BV, as well as AKI and pneumonia. As a result, the study delved into analyzing the key targets and pathways associated with these adverse events and offers valuable insights that can potentially guide the future clinical management of these complications. Declarations Data avaliability statement In addition to the data presented in the paper, further inquiries can be satified by the corresponding authors. Ethics statement The data shown in the study were approved by Shanghai Seventh People's Hospital. Content of the research did not violate the laws of any country or institution. Author contributions SH: Data curation, Formal analysis, Inveatigation, Supervision, Writing QL: Data curation, writing-review and editing YL: Writing-review and editing KS: Supervision, Funding acquisition, Editing WF: Metholodology,Funding acquisition, Editing Funding All authors declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the “Big Dipper” talent training program of the Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine under Grant No.BDX2022-01 and Shanghai Pudong New Area Health Commission traditional Chinese medicine science and technology innovation project under Grant No.PDZY-2023-1110. References Pawinska K, Czogala M, Skoczen S, Surman M, Rygielska M , Ksiazek T, et al. Gemtuzumab ozogamicin for relapsed or primary refractory acute myeloid leukemia in children-the Polish Pediatric Leukemia and Lymphoma Study Group experience. 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Treatment and diagnosis of chemotherapy-induced peripheral neuropathy: An update. Biomed Pharmacother. 147, 112671. doi:10.1016/j.biopha.2022.112671 D'Souza RS, Alvarez GAM, Dombovy-Johnson M, Eller J, Abd-Elsayed A. Evidence-based treatment of pain in chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep (2023) 27 (5), 99-116. doi:10.1007/s11916-023-01107-4 Patterson M., Dokouhaki P, Dumaine CS, MacKay R, Tai DJ. Brentuximab-induced acute interstitial nephritis: a case report. Can J Kidney Health Dis (2024) 11:20543581241300766. doi:10.1177/20543581241300766 Sato, Y., Oguchi, A., Fukushima, Y., Masuda, K., Toriu, N., Taniguchi, K., et al. CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. J Clin Invest (2022) 132(2):e146071. doi:10.1172/JCI146071 Sun N, Zhang M, Kong J, Li J, Dong Y, Wang X, et al. Dysregulated T-cell homeostasis and decreased CD30 + Treg proliferating in aplastic anemia. Heliyon (2024) 10 (15), e35775. doi:10.1016/j.heliyon.2024.e35775 Menéndez V, Solórzano JL, García-Cosío M, Cereceda L, Díaz E, Estévez M, et al. Mapping the spatial dynamics of the CD4 + T cell spectrum in classical hodgkin lymphoma. Mod Pathol (2024) 37 (9), 100551. doi:10.1016/j.modpat.100551. Gress AR, and Bold TD. TB granuloma: CD30 co-stimulation for CD4+ T cell co-operation. J Exp Med (2023) 220 (8), e20230547. doi:10.1084/jem.20230547 Gharaie S, Lee K, Newman-Rivera AM, Xu J, Patel SK, Gooya M, et al. Microbiome modulation after severe acute kidney injury accelerates functional recovery and decreases kidney fibrosis. Kidney Int (2023) 104 (3), 470-491. doi:10.1016/j.kint.2023.03.024 Foreman TW, Nelson CE, Sallin MA, Kauffman KD, Sakai S, Otaizo-Carrasquero F, et al. CD30 co-stimulation drives differentiation of protective T cells during Mycobacterium tuberculosis infection. J Exp Med (2023) 220 (8), e20222090. doi:10.1084/jem.20222090 Zhou C, Peng S, Lin A, Jiang A, Peng Y, Gu T, et al. Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. E Clinical Medicine (2023) 59, 101967.doi:10.1016/j.eclinm.2023.101967 Dumontet C, Reichert JM, Senter PD, Lambert JM, and Beck A. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov (2023) 22 (8), 641-661. doi:10.1038/s41573-023-00709-2 Jin Y, Schladetsch MA, Huang X, Balunas MJ, and Wiemer AJ. Stepping forward in antibody-drug conjugate development. Pharmacol Ther (2022) 229, 107917. doi:10.1016/j.pharmthera.2021.107917 Tables Tables 1 to 6 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files BVtables.docx SupplementmaterialsBV.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6876929","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":485715975,"identity":"3b7a0307-c383-48ae-bf94-daf39b52acf3","order_by":0,"name":"Huan Sun","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Huan","middleName":"","lastName":"Sun","suffix":""},{"id":485715977,"identity":"d5699ab6-49cf-4a51-ba22-54f840fd2365","order_by":1,"name":"Qiaoli Zhai","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Qiaoli","middleName":"","lastName":"Zhai","suffix":""},{"id":485715979,"identity":"f3cd3a44-a0ee-4417-bc45-f3f793f23ed3","order_by":2,"name":"Yuan Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Li","suffix":""},{"id":485715983,"identity":"b58e6ba4-7c97-4aba-9a42-950946be9679","order_by":3,"name":"Kourong Shi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Kourong","middleName":"","lastName":"Shi","suffix":""},{"id":485715984,"identity":"9cf8b03f-5a97-43bb-946e-7580bf6ae73c","order_by":4,"name":"Wei Fan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYHACNgYGAwYe9gbmAwc+VJCihecAW+LBGWeI1gIEPAd4jA/zthCh3uBG8rEHPwrqZHgkcj4c4G1gkOcXO4Bfi+SMtHTDHgM2Hh6J3A0HJHcwGM6cnYBfC79EjpkEjwEPj700UIvhGYYEg9sEtLBJ5H+T/GMgwcMjnfPgQGIbEVqAtrBJ8xgYgLQwHDhIjBbJnmdm0jIGCTw88s8MDjackSDsF4Pjyc8k3/yps+fhOfz4858KG3l+aQJa0IEEacpHwSgYBaNgFGAHANhQPyGJG3z+AAAAAElFTkSuQmCC","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Fan","suffix":""}],"badges":[],"createdAt":"2025-06-12 06:08:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6876929/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6876929/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87043371,"identity":"6e9b7542-bea4-4867-8af3-6fb56b33107e","added_by":"auto","created_at":"2025-07-18 14:15:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":16155,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow chart of screening ADE reports and ADEs of BV in the FAERS database (Q3 2011-Q2 2024). DEMO, patient demographic and administrative information; DRUG, BV information; REAC,adverse events; PS, primary suspect.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/cf70af14e3ee131031a85ae7.jpg"},{"id":87043372,"identity":"cd4203a3-9f31-415c-bfb4-f8b8f7fac01e","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21746,"visible":true,"origin":"","legend":"\u003cp\u003eDetection of ADE reports. (A) Cumulative incidence percents of ADE reports after first medication of BV over time. (B) Number of ADE reports after first medication of BV over time.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/16a2bb4642ae329f8bcd3d6d.jpg"},{"id":87043373,"identity":"dc01f0f3-c3cf-43e5-ba7c-e517d55d6651","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":40767,"visible":true,"origin":"","legend":"\u003cp\u003eDemographic characteristics of ADE reports in the FAERS database (Q3 2011- Q2 2024).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/b00f91a99815619c3fa79f35.jpg"},{"id":87044447,"identity":"7ecb45ba-4c91-475f-8cab-4498cb5d8b08","added_by":"auto","created_at":"2025-07-18 14:23:38","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":53511,"visible":true,"origin":"","legend":"\u003cp\u003eSignal detection at the SOC level. The bar chart represents cases of reported ADEs at each SOC level (Q3 2011-Q2 2024).\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/ad52be73083508205dccb4e5.jpg"},{"id":87043374,"identity":"d58b7147-3b9a-4477-add8-451ac2266776","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":27948,"visible":true,"origin":"","legend":"\u003cp\u003eSignal detection at the PT level. (A) The bar chart represents cases of reported ADEs at each PT level (Q3 2011-Q2 2024). (B) The forest diagram displays the top 10 PTs. (C) The venn diagram displays numbers of PT crossing calculated by four pharmacovigilance algorithms.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/b91bace0930dcae7e59b9a37.jpg"},{"id":87043376,"identity":"5e658115-3121-4049-bc25-a721e0f50a95","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":21051,"visible":true,"origin":"","legend":"\u003cp\u003eDetection of serious ADEs reports. (A) Cumulative incidence percents of serious ADE reports after first medication of BV over time. (B) Number of serious ADE reports after first medication of BV over time.\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/df7855b200e4fdde8b175451.jpg"},{"id":87043378,"identity":"9f12f135-fc51-46d2-9256-127dd1aa9bac","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":42109,"visible":true,"origin":"","legend":"\u003cp\u003eDemographic characteristics of serious ADEs reports in the FAERS database (Q3 2011-Q2 2024).\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/0ee58648263760d6ede91c4e.jpg"},{"id":87043380,"identity":"03e95576-4391-4973-8e5a-2376162aec62","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":45166,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork pharmacological analysis of ADEs. (A-B) GO and KEGG enrichments of peripheral neuropathy. (C-D) GO and KEGG enrichments of AKI.\u003c/p\u003e","description":"","filename":"8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/596ea8bc47c9693d4b3b60da.jpg"},{"id":89676740,"identity":"9f553e7b-3b00-4f0f-bb67-ed03cd479227","added_by":"auto","created_at":"2025-08-22 13:53:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":870222,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/9cbe3ed6-82ca-46eb-bb7e-078d9ef6d970.pdf"},{"id":87043377,"identity":"9f0ad81d-2e68-48d0-bf11-387e86744b92","added_by":"auto","created_at":"2025-07-18 14:15:38","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":59584,"visible":true,"origin":"","legend":"","description":"","filename":"BVtables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/2f3ccca8a5150faadf5053bd.docx"},{"id":87043381,"identity":"2cd58b02-169a-4b37-9331-ab2df3ed47fa","added_by":"auto","created_at":"2025-07-18 14:15:39","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22271702,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementmaterialsBV.doc","url":"https://assets-eu.researchsquare.com/files/rs-6876929/v1/4198682d6bb26c11994c9e92.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"A real-world pharmacovigilance study of brentuximab vedotin based on the FAERS database from 2011 to 2024","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe Food and Drug Administration (FDA) officially granted approval for the first ADC drug—Gemtuzumab ozogamicin in 2000. However, the drug was withdrawn from the market in 2010 due to severe side effects and later re-approved in 2017[1]. BV received FDA approval in 2011 and was introduced to the Chinese market in 2020.\u0026nbsp;With a wealth of clinical experience accumulated since its introduction, BV has been designated as a standard treatment option by the National Comprehensive Cancer Network (NCCN). Notably, BV marks the first FDA-approved drug for the treatment of systemic anaplastic large cell lymphoma (sALCL) and classical Hodgkin lymphoma (cHL) in the past 45 years[2]\u003csup\u003e.\u003c/sup\u003e BV is formulated with a monoclonal antibody designed to target CD30, coupled with monomethyl auristatin E (MMAE), a potent microtubule inhibitor[3]\u003csup\u003e.\u003c/sup\u003e As an ADC, BV possesses the ability to specifically identify and bind to cancer cells' surfaces. Once absorbed by these malignant cells, the linker molecule MMAE is triggered to release the drug in targeted circumstances, ultimately leading to the destruction of cancer cells\u0026nbsp;[4]. BV exhibits a prolonged circulation time within the bloodstream, effectively targeting and eradicating tumor cells expressing CD30. Leveraging its precise targeting mechanism on cancer cells, BV offers the advantages of minimized side effects and superior therapeutic efficacy compared to traditional chemotherapy agents.\u003c/p\u003e\n\u003cp\u003eHowever, there have been some ADEs during the application of BV. The relatively common ADEs are peripheral neuropathy and neutropenia. In addition, there have been numerous reports of hematotoxicity and neurotoxicity linked to the use of ADCs, and these effects may be related to the cytotoxic payload linker MMAE[5]. The mechanisms underlying these ADEs may be tied to \u0026nbsp;off-target effects of non-tumor cells, targeted antigens uptake of non-tumor cells or non-target antigens uptake of non-tumor cells [6]. It is also worth noting that MMAE has to been shown to be nephrotoxicity [7]. ADCs like Disitamab vedotin explicitly warn about renal-related ADEs in their instructions, including the development of proteinuria, hematuria, and renal dysfunction. These renal ADEs might be attributed to the hepatic and renal metabolism of the conjugates[8]. In a Phase III trial involving patients with cHLs who had undergone autologous hematopoietic stem cell transplantation, it was found that 67% of patients experienced varying degrees of peripheral neuropathy following treatment with BV [9].\u003c/p\u003e\n\u003cp\u003ePeripheral neuropathy is one of the main reasons for the withdrawal of BV, including peripheral sensory neuropathy and peripheral motor neuropathy, which is caused by brain and peripheral nerve injury[10-11]. It often manifested as weakness, numbness and pain in the hands and feet, and may also impact other bodily functions like digestion and urination [12]. It may be linked to an increase in inflammatory factors and a decrease in peripheral nerve growth factors [13]. When sensory nerves are affected, individuals may experience limb hypoesthesia or paresthesia, which can persist long after the offending medication has been discontinued [14].\u003c/p\u003e\n\u003cp\u003eAcute Kidney Injury (AKI) is a condition characterized by a sudden and rapid decline in renal function over a period of 1-7 days, lasting for more than 24 hours. Symptoms of AKI often include decreased urine output and swelling, among others. Common causes of AKI include insufficient renal blood flow, exposure to toxic substances that damage the kidneys, and kidney infections [15]. The onset of AKI is swift and can lead to complications such as pleural effusion and muscle weakness [16]. Research has shown that individuals with pre-existing chronic kidney disease are at a higher risk of developing AKI compared to those with healthy kidneys. Chronic kidney disease is identified as a significant risk factor for the development of AKI [17].\u003c/p\u003e\n\u003cp\u003eFAERS is a database that plays a crucial role in the collection and analysis of ADEs associated with marketed drugs. It encompasses a wealth of information on ADEs, drug abuse, misuse, and more, serving as a vital tool for monitoring drug safety and providing guidance for the rational use of drugs clinically [18]. However, current studies on ADEs of BV may not be in-depth enough. The study seeks to address this gap by conducting a comprehensive analysis of the connections between BV and its associated ADEs. In addition to this, the study focuses on two specific ADEs: peripheral neuropathy, a commonly observed side effect, and acute kidney injury (AKI), a newly reported ADE. By examining the underlying targets and pathways related to these ADEs, the research aims to provide insights that can guide the rational use of BV and improve patient outcomes in the future.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Data sources and processing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this research was sourced from the American Standard Code for Information Interchange\u0026nbsp;Ⅱ (ASCⅡ) , retrieved from the FAERS database spanning from Q1 2004 to Q2 2024. The collected data was then transferred into SAS 9.4 software for thorough analysis and interpretation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eADE reports were screened by searching “DRUGNAME--- Brentuximab vedotin” as the primary suspect drug. The duplicate reports were removed following the guidelines provided by the U.S. FDA[19]. Since BV was first marketed in 2011, the study focused on data obtained from the FAERS database, specifically from Q3 2011 to Q2 2024,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Application of MedDRA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe latest version of the Medical Dictionary for Regulatory Activities (MedDRA 27.0) was utilized to encode the ADEs listed in the FAERS database. The names of PTs were also revised and recalibrated. The SOCs and PTs served as the criteria for assessing and analyzing the data further.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Data analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research utilized a case-non-case analysis method to identify potential signals of ADEs. A 2×2 contingency table was presented for disproportionality analysis (Table 1 ). Several algorithms, including ROR, PRR, BCPNN, and MGPS, are commonly utilized for detecting signals of ADEs[20]. These algorithms are employed to quantify the strength of the relationship between BV and various ADEs, demonstrating a level of credibility. Of these algorithms, ROR is particularly prominent and is frequently utilized in signal detection (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Target acquisition and Pathway Analysis for Peripheral Neuropathy, Acute Kidney Injury (AKI), and Pneumonia\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGeneCards database (https://www.genecards.org/) was retrieved to obtain disease-related targets by searching the key terms “Peripheral neuropathy”,“Acute kidney injury”, and “Penumonia” respectively. All targets obtained were integrated in an excel spreadsheet, with any duplicate genes removed to ensure accuracy of the data. And finally key genes were obtained through the correction of the Uniprot database. Subsequently, the information on the key genes was inputted into the DAVID database (https://david.ncifcrf.gov/summary.jsp), with the settings adjusted to focus on \"OFFICIAL_GENE_SYMBOL\" for Homo sapiens. The Gene Ontology (GO) tool was employed to provide insights into the functions of the key proteins in terms of biological processes (BP), cellular components (CC), and molecular functions (MF). Additionally, KEGG pathway enrichment analysis was utilized to identify pathways that are linked to the diseases of interest.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Total ADE reports among BV users in the FAERS database from Q3 2011 to Q2 2024\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the study, ADE reports (\u003cem\u003en\u003c/em\u003e=6,515) and ADEs related to BV (\u003cem\u003en\u003c/em\u003e=21,055) were finally obtained from the FAERS database between Q3 2011 and Q2 2024 (Figure 1). It was observed that half of the ADE reports occurred within 21 days after the first medication of BV. Furthermore, the ADE reports continued for up to a year following the initial medication (Figure 2A). And ADE reports accounted for a relatively high proportion within 30 days after first medication of BV (\u003cem\u003en\u003c/em\u003e=1,577, 59.95%) (Figure 2B). These findings highlight the importance of patient vigilance and prompt communication between patients and healthcare providers in cases of discomfort, particularly in the early stages of BV treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Demographic characteristic analysis of ADE reports\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExcluding reports that were unclear or lacked sufficient detail, it was found that a higher proportion of male patients (\u003cem\u003en\u003c/em\u003e=2,729, 41.89%) experienced adverse events compared to female patients. Additionally, patients between the ages of 18-44 years were more likely to report adverse events (\u003cem\u003en\u003c/em\u003e=1,325, 20.34%) than other age groups. Among different occupations, doctors were the most frequent reporters of adverse events (\u003cem\u003en\u003c/em\u003e=3,406, 52.28%). The data also showed that during 2011 to 2024, the number of adverse events reported in 2020 was significantly higher (\u003cem\u003en\u003c/em\u003e=823). \u0026nbsp;Furthermore, the severity of ADEs caused by BV appeared to be relatively serious (Figure 3). The study also examined the distribution of target patients in various regions around the world (Figure S2). These findings indicate the importance of closely monitoring patients who are prescribed BV to ensure their safety and well-being.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 The signals of ADEs detected at the SOC level\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the SOC level, the most common reported adverse events included general disorders and administration site conditions, infections and infestations, and investigations. These accounted for 13.91%, 10.06%, and 9.79% of the total number of adverse events, respectively (Figure 4). When ranked by the reporting odds ratio (ROR), the top 5 SOCs with the highest ROR values were infections and infestations (20.48%), investigations (15.26%), nervous system disorders (8.43%), respiratory, thoracic and mediastinal disorders (8.03%), and blood and lymphatic system disorders (6.83%) (Table 3 ).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 The signals of ADEs detected at the PT level\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the PT level, Pyrexia, Peripheral neuropathy, Febrile neutropenia were observed relatively frequent (Figure 5A\u0026nbsp;). After excluding PTs unrelated to ADEs such as “Off label use” and then sorted according to ROR values in descending order, the top 5 PTs were peripheral sensory neuropathy, pneumocystis jirovecii pneumonia, febrile neutropenia, myelosuppression, and peripheral neuropathy. It is worthy noted that pancytopenia, leukopenia, sepsis, aspartate aminotransferase increased, alanine aminotransferase increased, pleural, and effusion were not mentioned in the instruction (Table 4\u0026nbsp;). A forest plot diagram was utilized in order to represent the differences betweenvarious ADEs more intuitively (Figure 5B\u0026nbsp;) . Additionally, a Venn diagram illustrating PT overlaps calculated by four pharmacovigilance algorithms was provided (Figure 5C\u0026nbsp;). More detailed information regarding ADE signal strength at the PT level was shown in the supplementary material (Table S1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Signal detection of serious ADE reports\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsistent with the genral trend of ADE reports, 50% of all reports for serous ADEs occurred within 21 days of starting BV medication (Figure 6A\u0026nbsp;). A significant proportion of serious ADE reports (\u003cem\u003en\u003c/em\u003e=1,524, 56.63%) were reported within 30 days of starting BV medication (Figure 6B\u0026nbsp;) \u0026nbsp;.\u003c/p\u003e\n\u003cp\u003eAfter excluding any reports that lacked clarity, it was found that the percentage of male patients (\u003cem\u003en\u003c/em\u003e=2,523, 43.15%) was higher than that of female patients. Addtionally, the proportion of patients aged 18-44 years old was higher (\u003cem\u003en\u003c/em\u003e=1,278, 21.78%) than other age groups.Among individuals from different occupations, doctors reported the highest number of serious adverse events(\u003cem\u003en\u003c/em\u003e=3,192, 54.4%). During 2011-2024, the number of serious adverse events reported in 2020 was higher (\u003cem\u003en\u003c/em\u003e=764) (Figure 7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the SOC level, sorted according to ROR values in descending order, the top 5 serious SOCs were infections and infestations (20.81%), investigations (14.45%), nervous system disorders (9.25%), blood and lymphatic system disorders (7.51%) , \u0026nbsp;and respiratory,thoracic and mediastinal disorders (7.51%) (Table 5 ). Similarly, at the PT level, the top 5 serious PTs were pyrexia, febrile neutropenia, peripheral neuropathy, neutropenia, and white blood cell count decreased (Table 6 ). The table illustrating the signal strength of serious ADEs at the PT level was shown in the supplementary material (Table S2). These findings emphasize the importance of monitoring and paying close attention to patients experiencing the aforementioned serious ADEs while they are being treated with the medication of BV.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 Analysis of potential targets and pathways of peripheral neropathy and AKI caused by BV\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive analysis of peripheral neuropathy-related targets revealed a total of 1262 GO items. Within the BP category, there were 938 items identified, with a focus on positive regulation of gene expression, signal transduction, and negative regulation of the apoptotic process. In terms of CC category, 171 items were identified, with a predominant presence in the cytosol, cytoplasm, and plasma membrane. The MF category encompassed 153 items, with a strong emphasis on protein binding, identical protein binding, and ATP binding (Figure 8A). Subsequently, pathway analysis was conducted by using the database, a total of 209 pathways were enriched and 176 related pathways were screened according to \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01, among which the top 5 pathways were pathways of neurodegeneration - multiple diseases, AGE-RAGE signaling pathway in diabetic complications, amyotrophic lateral sclerosis, PI3K-Akt signaling pathway, and HIF-1 signaling pathway (Figure 8B).\u003c/p\u003e\n\u003cp\u003eIn the analysis of AKI-related targets, a total of 1,492 GO items were screened. Within the Biological Process (BP) category, there were 1,198 specific items identified. These items predominantly revolved around the topics of positive regulation of gene expression, signal transduction, and negative regulation of apoptosis.The CC category included 142 items, which mainly involed ctosol,cytoplasm,and nucleus. The MF category included 152 items, which mainly involved identical protein binding, metal ion bingding, and ATP binding (Figure 8C). Subsequently, this database was utilized for pathway analysis, resulting in a total of 191 pathways being enriched. Among these, 162 pathways were identified as being significantly related based on a significance level of P \u0026lt; 0.01. The top 5 pathways identified were the PI3K-Akt signaling pathway, HIF-1 signaling pathway, FoxO signaling pathway, JAK-STAT signaling pathway, and endocrine resistance(Figure 8D).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, the analysis of ADEs associated with the use of BV revealed several noteworthy ADEs that were not specifically mentioned in the product instructions, such as leukopenia (ROR 5.12, PRR 5.10, IC 2.35, 95% EBGM 5.09), sepsis (ROR 4.83, PRR 4.80, IC 2.62, 95% EBGM 4.79), aspartate aminotransferase increased (ROR 3.99, PRR 3.98, IC 1.99, 95% EBGM 3.98), alanine aminotransferase increased (ROR 3.69, PRR 3.68, IC 1.88, 95% EBGM 3.68), and pleural effusion (ROR 3.58, PRR 3.57, IC 1.83, 95% EBGM 3.56) .\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;In addition, 82 cases of tachycadia related to BV administration were reported in FAERS database. Previous studies have found that microtubule inhibotors can cause cardiac toxicity, including myocardial infarction, heart failure, and arrhythmia[21-22].Therefore, the occurrence of tachycardia in patients treated with BV may be attributed to the pharmacological properties of MMAE. In addition to tachycardia, the FAERS database also documented 248 cases of pneumonia associated with BV. A recent case report described a 40-year-old woman with cutaneous T-cell lymphoma who developed pneumonia and diffuse alveolar injury following BV treatment[23]. The issue of drug-related pneumonia is a significant concern, characterized by inflammatory reactions in the lungs triggered by drugs and their metabolites through direct cytotoxic effects or allergic reactions. Alongside brentuximab vedotin, several chemotherapy agents such as bleomycin, cyclophosphamide, vinblastine, and etoposide have been implicated in causing drug-related pneumonia [24-25]. Chemotherapy-induced pneumonia can be attributed to various factors. Firstly, chemotherapy often compromises immune function, rendering patients more susceptible to infections. Secondly, frequent hospital visits and prolonged hospital stays further increase the risk of pneumonia acquisition. Additionally, chemotherapy-induced pneumonia can be linked to factors such as neutropenia, mucosal damage, and structural alterations in the lungs [26-27]. Beyond chemotherapeutic agents, certain antibiotics like amikacin have also been associated with the development of pneumonia post-administration[28].\u003c/p\u003e\n\u003cp\u003eCurrently, there is a growing number of research on peripheral neuropathy caused by the use of BV [29-31] . Commonly prescribed drugs for treating peripheral neuropathy resulting from chemotherapy include duloxetine, pregabalin, and opiums[32]. However, these drugs still have some side effects. For instance, duloxetine, primarily used to treat depression, has been found to alleviate neuralgia; however, it can lead to adverse effects such as increased blood pressure, insomnia, headaches, and dysuria [33]. Similarly, long-term use of pregabalin and opioids can potentially result in addiction. A concerning finding from the FAERS database revealed 110 reported cases of AKI associated with BV use. Strikingly, AKI was not listed in the prescribing information for BV, highlighting it as a newly identified ADE. In 2024, a case was reported detailing a 73-year-old man with a medical history of hypertension, chronic kidney disease, and benign prostatic hyperplasia who experienced AKI following BV treatment for mycosis fungoides [34]. A study found that CD30-deficient mice exhibited reduced inflammation in a kidney injury model compared to normal mice[35]. Additionally, research has indicated that CD4\u003csup\u003e+\u003c/sup\u003e cells play a role in the pathogenesis of AKI, with a connection observed between CD30 and CD4\u003csup\u003e+\u003c/sup\u003e[36-37]. Therefore, the development of AKI due to BV may involve the regulatory influence of CD30 on CD4\u003csup\u003e+\u003c/sup\u003e cells[38-40]. It is important to note that many chemotherapy drugs are eliminated through the kidneys, emphasizing the need for caution in patients with renal impairment following BV administration. In conclusion, further research is warranted to elucidate the relationships and potential mechanisms linking BV to AKI.\u003c/p\u003e\n\u003cp\u003eThere are certain limitations associated with the FAERS, a database comprised of ADEs reported artificially. Some of these limitations include incomplete reporting information, inaccuracies in reporting formats, and redundant reports [41]. For instance, there have been instances of inaccurate reporting, such as the confusion between peripheral neuropathy and peripheral sensory neuropathy. Despite these limitations, BioVeris (BV) stands out for its long history of clinical use, wide therapeutic ranges, and effectiveness in treatment. It proves challenging to develop alternative drugs with fewer ADEs compared to BV. Although Antibody-Drug Conjugates (ADCs) are still under ongoing research, there are measures that can be implemented to reduce toxicity. These include the use of small molecule drugs with different mechanisms of action and the enhancement of drug delivery uniformity and pharmacokinetic characteristics through the application of site-specific coupling technologies[42-43].\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThe study focused on collecting and analyzing ADEs of BV in the FAERS database from Q3 2011 to Q2 2024.The findings of this study emphasize the importance for clinicians and clinical pharmacists to closely monitor both common and newly emerging ADEs linked to BV use. Of particular concern is the relatively high incidence rate of peripheral neuropathy attributed to BV, as well as AKI and pneumonia. As a result, the study delved into analyzing the key targets and pathways associated with these adverse events and offers valuable insights that can potentially guide the future clinical management of these complications.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData avaliability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn addition to the data presented in the paper, further inquiries can be satified by the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data shown in the study were approved by Shanghai Seventh People's Hospital. Content of the research did not violate the laws of any country or institution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSH: Data curation, Formal analysis, Inveatigation, Supervision, Writing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQL: Data curation, writing-review and editing\u003c/p\u003e\n\u003cp\u003eYL: Writing-review and editing\u003c/p\u003e\n\u003cp\u003eKS: Supervision, Funding acquisition, Editing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWF: Metholodology,Funding acquisition, Editing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the “Big Dipper” talent training program of the Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine under Grant No.BDX2022-01 and Shanghai Pudong New Area Health Commission traditional Chinese medicine science and technology innovation project under Grant No.PDZY-2023-1110.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePawinska K, Czogala M, Skoczen S, Surman M, Rygielska M , Ksiazek T, et al. Gemtuzumab ozogamicin for relapsed or primary refractory acute myeloid leukemia in children-the Polish Pediatric Leukemia and Lymphoma Study Group experience. Front Immunol (2023)14, 1268993. doi:10.3389/fimmu.2023.1268993\u003c/li\u003e\n\u003cli\u003eLiu W, Wu J, Ming X, Zhang Q, Zhou D, Zheng R, et al. 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Stepping forward in antibody-drug conjugate development. Pharmacol Ther (2022) 229, 107917. doi:10.1016/j.pharmthera.2021.107917\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"brentuximab vedotin, FAERS, pharmacoviligilance, network pharmacology, peripheral neurophthy, acute kidney injury, pneumonia","lastPublishedDoi":"10.21203/rs.3.rs-6876929/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6876929/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) that targets CD30 and is primarily used in the treatment of CD30-positive lymphoma. While BV has shown success in treating patients with this type of lymphoma, there have been reports of serious adverse drug events (ADEs) associated with its use. This study aims to investigate the ADEs related to BV reported in the FDA Adverse Event Reporting System (FAERS) database from the third quarter of 2011 (Q3 2011) to the second quarter of 2024 (Q2 2024). Furthermore, the possibility and potential targets of peripheral neuropathy and acute kidney injury (AKI) caused by BV were analyzed. Targets associated with occurrence of ADEs were obtained by applying GeneCards database and key genes were enriched by GO and KEGG methods. A total of 6,515 adverse event reports and 21,055 ADEs related to BV were retrieved, half of which occurred within 21 days after first medication. The most frequently preferred terms (PTs) included peripheral sensory neuropathy, pneumocystis jirovecii pneumonia, and febrile neutropenia. The analysis of FAERS data allows for a thorough understanding of the real-world use of BV and helps to proper utilize and manage these potential adverse events.","manuscriptTitle":"A real-world pharmacovigilance study of brentuximab vedotin based on the FAERS database from 2011 to 2024","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 14:15:33","doi":"10.21203/rs.3.rs-6876929/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"47e0e7c4-592d-4f0a-be95-94ec4d2a2f44","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-22T13:53:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 14:15:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6876929","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6876929","identity":"rs-6876929","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}