Avacopan-Associated Hepatotoxicity: Clinical Signal, Liver Injury Patterns, and Plausible Mechanisms

Avacopan, an oral selective C5a receptor antagonist used as a glucocorticoid-sparing adjunct in severe active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, has been linked to a potential hepatobiliary safety concern. This critical narrative review summarizes clinical, real-world, pharmacovigilance, and regulatory evidence on avacopan-associated liver injury, with emphasis on reported injury patterns and plausible mechanisms. The review was informed by a targeted bibliographic search of PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), Embase, Scopus, and Web of Science, complemented by regulatory documents, prescribing information, FDA and European Medicines Agency (EMA) safety communications, and LiverTox. Pre-approval clinical trials first identified hepatic adverse events more frequently in avacopan-exposed patients than in comparators, although phenotypic characterization was limited. Subsequent case reports, observational cohorts, and FDA Adverse Event Reporting System (FAERS)-based pharmacovigilance analyses strengthened this concern. Recent large-scale FAERS evaluations have included more than 3,000 avacopan-related adverse event reports, including analyses of 3,529 reports and 3,150 reports in which avacopan was recorded as the primary suspect drug. Across these analyses, hepatobiliary events included abnormal liver function, elevated transaminases, jaundice, cholestasis, drug-induced liver injury (DILI), and vanishing bile duct syndrome (VBDS). Although hepatocellular and mixed patterns have been reported, the most clinically concerning phenotype is cholestatic-biliary injury, including prolonged jaundice, small bile duct injury, ductopenia, and VBDS, occasionally with fatal outcomes. Reported onset most often occurred within the first one to three months of therapy, although later presentations were also described. The FDA and EMA have responded by strengthening product safety information and recommending baseline liver assessment and close monitoring, particularly during the first six months of treatment. The mechanism remains unknown; the most plausible interpretation is multifactorial idiosyncratic DILI, potentially influenced by host susceptibility, CYP3A-related exposure, drug-drug interactions, and impaired biliary recovery in severe cases. Because causal attribution is complicated by concomitant immunosuppressive and antimicrobial therapies, avacopan should be used with careful baseline evaluation, serial liver monitoring, and prompt interruption when clinically significant liver injury is suspected.