Adverse Reaction Signals Mining of Vonoprazan: A Pharmacovigilance Study Based on FAERS

Background . Vonoprazan is a novel selective and noncompetitive oxidative-reduction state proton pump inhibitor (PPI), known as a potassium-competitive acid blocker (P-CAB). Due to its novelty, the clinical application of vonoprazan is relatively limited, and its long-term safety and adverse efects still need to be further studied and confrmed. Methods . We used the data from the FDA adverse eventreporting system (FAERS) from 2015 to 2022. Disproportionality method including calculation of the reporting odds ratio (ROR) and calculation of the information component (IC) was used to detect potential adverse drug reactions (ADRs). In preferred terms, the signifcant signals are ranked in the following order: Plateletcrit increased (ROR 1447.3 IC 36.62), benign duodenal neoplasm (ROR 11157.84 IC 36.40), gallbladder volvulus (ROR 964.77 IC 36.20), myopathy endocrine (ROR 723.58 IC 35.88), pernio-like erythema (ROR 723.58 IC 35.88), septic coagulopathy (ROR 723.58 IC 35.88), and so on. In SOCs, the signifcant signals are ranked in the following order: hepatobiliary disorders (ROR 5.65 IC 29.15), metabolism and nutrition disorders (ROR 2.78 IC 28.12), blood and lymphatic system disorders (ROR 2.73 IC 28.12), investigations (ROR 2.19 IC 27.76), endocrine disorders (ROR 2.09 IC27.76), gastrointestinal disorders (ROR 1.87 IC 27.52), and so on. Conclusion . Despite its potential advantages, there is still limited clinical experience with vonoprazan, and the long-term safety and adverse efects of this drug are not fully understood. Further studies are needed to confrm its safety and efcacy in a larger patient population and to establish its role in the management of acid-related disorders. In the meantime, careful monitoring and patient education are recommended for those who are prescribed vonoprazan.


Introduction
Vonoprazan is a novel selective and noncompetitive oxidative-reduction state proton pump inhibitor (PPI), known as a potassium-competitive acid blocker (P-CAB) [1].Te metabolism of vonoprazan predominantly occurs through cytochrome P450 (CYP) 3A4, with additional contributions from CYP2B6, CYP2C19, CYP2D6, and SULT2A1, resulting in the formation of inactive metabolites [2].Compared to traditional PPIs, vonoprazan has a faster onset of action, longer duration of action, and stronger acidsuppressive efect [3,4].As a potassium-competitive acid blocker, vonoprazan acts on a diferent site of the proton pump than traditional PPIs, making it a promising option for patients who are resistant or partially responsive to traditional PPI therapy.In addition, its fast onset and long duration of action may provide more efective relief for patients with gastroesophageal refux disease (GERD) or other acid-related disorders.However, it just has been available in the market in Japan since February 2015 [1], so due to its novelty, the clinical application of vonoprazan is relatively limited, and its long-term safety and adverse efects still need to be further studied and confrmed.
Te FDA adverse event reporting system (FAERS) is a database that contains information on adverse events and medication errors that have been reported to the US Food and Drug Administration (FDA).Te database was created to support the FDA's postmarketing safety surveillance program for all approved drug and therapeutic biologic products.FAERS collects adverse event reports from a variety of sources, including physician, pharmacist, consumer and health-professional.Te reports contain information on the patient, the drug or biologic product involved, and the adverse event or medication error.Te database also includes information on the outcome of the event, such as hospitalization or death.FAERS is an important tool for identifying potential safety issues with drugs and biologic products.Te FDA uses the database to monitor the safety of products after they have been approved for use and to take appropriate regulatory action if necessary.Researchers and healthcare professionals can also use the database to conduct safety analyses and identify potential drug interactions or adverse events.
In this study, we conducted a pharmacovigilance analysis of vonoprazan using the FAERS data from 2015 to 2022, with the objective of ofering guidance to clinicians and patients on the appropriate usage of vonoprazan.

Materials and Methods
Te data for this study were the FAERS, conducted by the U.S. Food and Drug Administration (FDA), which aimed to surveil the safety of drug and therapeutic biologic products after postmarketing.Tis system collected demographic information, drug/biologic information, adverse event, outcomes for the event, and others are necessary for surveillance.All details of data are available on the FAERS website (https://www.fda.gov/drugs/drug-approvals-anddatabases/fda-adverse-event-reporting-system-faers).
In the period encompassing from 2015 to 2022, a total of 12,851,637 instances were documented, consisting of adverse event reports regarding vonoprazan, as reported by consumers and healthcare professionals.First, to prevent duplication of adverse event reports, as a single adverse event can be reported in multiple reports including follow-up reports for individual cases, we removed duplicate data based on priority rules, specifcally, caseid < fda_dt < primaryid.Also, we deleted some special cases according to the text fle that lists deleted fles since 2019 quarter one for various reasons including combining cases.Second, in the drug fle, we searched some terms in the list of drugname and prod_ai for vonoprazan such as "Vonoprazan," "Vonoprazan fumarate," "Takecab," and so on.We have collected 3732 cases of adverse reactions related to the use of vonoprazan as a treatment approach.Tird, we merged the three fles of drug, demo, reac via primaryid.Finally, we got 2595 cases including 10,453 reports of vonoprazan adverse events (AEs).Te reported data are standardized and classifed using the preferred terms (PTs) and system organ classes (SOCs) from the Medical Dictionary for Regularly Activities (MedDRAs) [5].Te overall workfow of this study is shown in Figure 1.

Statistical Analysis.
We used disproportionality method including calculation of the reporting odds ratio (ROR) and calculation of the information component (IC) to detect potential ADRs. 1 ADR signal was prompted when the evaluation criteria were met.Te ROR approach is based on the assumption that the reporting of AEs follows a twoby-two contingency table.Te IC method is based on the assumption that the use of a drug and the occurrence of an adverse event are independent.When a target drug is more likely to induce a target AE than all other drugs, it will typically get a higher score due to a higher disproportionality.Te disproportionality method is based on the following two-by-two contingency table (Table 1), and the formulas for ROR and IC are listed as follows (Table 2).All analyses were conducted using R (https://www.R-project.org; version 4.2.2).

Ethical Statements
Te data for this study were obtained solely from published FAERS data, eliminating the need for collecting raw data.As a result, Ethics Committee approval was deemed unnecessary.Te data sources used in this study were previously approved by the local Ethics Committee and adhered to local laws.In addition, all participants provided informed consent by signing the necessary documentation.

Basic Information of AE Report.
Ultimately, we got 2595 AE reports of vonoprazan.Te basic information of AE reports are shown in Table 3. Tere are 1392 patients with ARE who were men, accounting for 53.64%.Te proportion of old patients (age ≥ 65 year) was highest in all groups.Te number of annual reports has increased every year since 2015, with a maximum of 1077 cases in 2022.Most reported persons were medical professionals.2538 of 2595 cases reported 4140 AE outcomes including 1639 (39.59%) hospitalization and 1543 (37.27%) other serious important medical events.

Adverse Reaction Frequency Analysis.
Of the 2,595 reports, 10,453 AEs were reported.Te events that occur with a relatively high frequency are diarrhea, decreased appetite, pyrexia, interstitial lung disease, and pneumonia.AEs involved a total of 27 SOCs such as gastrointestinal disorders, nervous system disorders, vascular disorders, hepatobiliary disorders, and others (see Figures 2 and 3 for details).4 and 5), and we compared PTs with the adverse reactions in the drug package insert.Under the premise of removing PT according to the indication from professiona, adverse reactions not mentioned in the package insert were marked with an asterisk ( * ).

Discussion
Vonoprazan is a recently approved competitive potassiumcompetitive acid blocker (P-CAB) that works by competitively blocking the potassium-binding site of H+, K+-ATPase.Compared to traditional organic proton pump inhibitors (PPIs), vonoprazan has the advantages of fast onset, long-lasting acid suppression, minimal individual variation in acid suppression, and low susceptibility to the efects of diet.However, due to its novelty, there is a lack of clinical data, so this study discusses the potential adverse reactions of vonoprazan by mining the FAERS database for AE reports from 2015 to 2022.

Basic Information of AE Report.
In the table of basic information of AE report, the male populace and the overall number of individuals exceed their female counterparts.Tis may be attributed to the fact that vonoprazan's primary indication is for the treatment of gastroesophageal refux disease, which is more prevalent among men and the elderly [6].
As time progresses, with vonoprazan gradually entering the market and more individuals utilizing it, the number of AEs has increased yearly.Te majority of such reports are provided by healthcare professionals, thereby ensuring the reliability of the data.Te main outcome of vonoprazaninduced adverse reactions is hospitalization.

Adverse Reaction Frequency Analysis.
In the adverse reaction frequency analysis, the majority of reported cases pertain to the documented adverse efects in the medication's package insert.For instance, diarrhoea, decreased appetite, pyrexia, and nausea fall under the category of gastrointestinal disorders; anaemia and platelet count decreased are classifed as blood and lymphatic system disorders; and hepatic function abnormal is grouped under hepatobiliary disorders.Tis suggests that gastrointestinal reactions and blood and lymphatic system disorders, as well as hepatobiliary disorders, are among the more commonly observed adverse reactions associated with vonoprazan.

PTs and SOCs Disproportionality Analyses.
Te new PT signal we have excavated has been sorted according to ROR.Both plateletcrit increased and pernio-like erythema have been recorded in the drug manual's adverse reactions section.In addition, the SOC signals we have discovered, namely, hepatobiliary disorders, blood and lymphatic system disorders, and gastrointestinal disorders, have also been mentioned in the manual, reminding us to be mindful of potential risks.
In the excavated signals, benign duodenal neoplasm (ROR1157.84IC36.40), hypergastrinaemia (ROR579.47IC 35.62), and duodenal polyp (ROR 195.51 IC34.22) are noteworthy.Currently, it is known that during conventional PPI therapy, the level of gastrin increases [7].Terefore, it is necessary to consider the increased risk of elevated gastrin levels and gastric mucosal hyperplasia with vonoprazan, which is greater than with conventional PPIs [8].Research studies have confrmed that PPI-related hypergastrinemia in mice may promote gastric cancer through gastrin receptors and PPI increases the risks of polyp [9,10].To our knowledge, there has been a reported case of central depressed-type gastric adenocarcinoma discovered during maintenance therapy for refux esophagitis with P-CAB, as well as several reports of benign gastric polyps caused by vonoprazan, which gradually disappear after discontinuation [11][12][13].In a study published in BMC Gastroenterology [14], the administration of vonoprazan led to an elevation in serum gastrin levels.Te histopathological scrutiny of gastric mucosa revealed that hyperplasia of parietal, foveolar, and G cells was more prevalent with vonoprazan compared to lansoprazole during the 156th week of the maintenance phase.Nevertheless, we lack sufcient data concerning long-term adverse events, such as the risk of neuroendocrine tumors or gastric cancer resulting from heightened gastrin levels during vonoprazan therapy.Te association between oral P-CABs and cancer development also remains ambiguous.However, the signal extraction from the FAERS database through this study implies that we ought to exercise prudence in relation to the risk of hypergastrinemia and its associated polyps and gastrointestinal malignancies that may be instigated by vonoprazan.
Vonoprazan may share a mechanism with other PPIs that reduces iron absorption, potentially causing hypoferritinemia [15].PPIs such as vonoprazan act by blocking the proton pump that produces gastric acid in the stomach [15][16][17][18].While this is benefcial for conditions such as GERD, it can also decrease the absorption of certain minerals and nutrients, including iron.Iron is best absorbed in an acidic environment, so when gastric acid production is reduced, iron absorption may also decrease.As a result, individuals taking vonoprazan or other PPIs who cannot obtain sufcient iron from their diet or supplements may be at an increased risk of developing hypoferritinemia and increased plateletcrit.
Although vonoprazan itself does not directly cause antibiotic-associated colitis, evidence suggests that the use of proton pump inhibitors (PPIs) such as vonoprazan may increase the risk of developing this disease.Antibioticassociated colitis is a type of colonic infammation caused by overgrowth of Clostridium difcile (C.difcile) following antibiotic treatment [19].Antibiotics disrupt the normal balance of bacteria in the gut, allowing for overgrowth of C. difcile and subsequent infection.PPIs such as vonoprazan can alter the normal gut microbiota, which may increase the risk of developing C. difcile infection [20].In addition, PPIs can lower the acidity of the stomach, which may increase the survival rate of C. difcile in the stomach and intestines [21].Several studies have found an increased risk of C. difcile-associated diarrhea or colitis in patients taking PPIs (including vonoprazan) [20][21][22].Tis risk is In light of the aforementioned, during the administration of vonoprazan, it is imperative to exercise vigilance regarding the potential occurrence of associated adverse reactions.Regularly engaging in gastroscopic examinations as well as relevant diagnostic procedures is paramount in order to forestall the manifestation of severe adverse efects.

Limitation.
Several limitations are inherent in this study: the FAERS database relies solely on voluntary reporting, and as such, not all adverse events may be reported.Tis means that the database may not accurately refect the true incidence of adverse events.In addition, the FAERS database does not take into account confounding factors that may impact the incidence of adverse events, such as patient demographics, comorbidities, and concomitant medications.As a result, it is essential to exercise caution when using FAERS and to evaluate potential ADR signals using clinical expertise.

Conclusion
Despite its potential advantages, there is still limited clinical experience with vonoprazan, and the long-term safety and adverse efects of this drug are not fully understood.Further studies are needed to confrm its safety and efcacy in a larger patient population and to establish its role in the management of acid-related disorders.In the meantime, careful monitoring and patient education are recommended for those who are prescribed vonoprazan.

Figure 1 :
Figure 1: Te basic workfow of this study.

Table 1 :
A two-by-two contingency table for a drug-adverse event combination.

Table 2 :
Summary of two algorithms used for signals detection.

Table 3 :
Basic information of AE report.

Table 5 :
Top signifcant signals on the SOC level.