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Background <p>Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), including cholangitis, a rare but clinically severe hepatobiliary phenotype. Whether potassium-competitive acid blockers (PCABs) such as vonoprazan are associated with hepatobiliary adverse-event reporting among ICI-treated patients remains unclear.</p> Methods <p>We performed a READUS-PV–compliant case–noncase disproportionality analysis using VigiBase, the WHO global individual case safety report database (inception through December 1, 2025; MedDRA v27.1). Adjusted reporting odds ratios (aRORs) were estimated for composite liver injury and a custom cholangitis-related endpoint for vonoprazan, proton pump inhibitors (PPIs), and histamine-2 receptor antagonists (H2RAs). The primary analysis was restricted to ICI-exposed reports and adjusted for age, sex, region, hepatotoxic co-medications, and ICI class. Sensitivity analyses addressed treatment intensity, microbiome-modifying co-medications, regional restriction, endpoint definition, sparse-data bias, and ICI subgroup. Six additional irAE categories were analyzed as comparator outcomes.</p> Results <p>Among 295,671 ICI-exposed reports, 1098 co-reported vonoprazan and 1186 reports met the cholangitis-related endpoint. Cholangitis was reported in 35 of 1098 vonoprazan-exposed reports (3.19%) versus 0.39% of ICI reports without vonoprazan. Vonoprazan was associated with increased cholangitis reporting (aROR 2.79; 95% CI 1.93–4.02; <i>P</i> &lt; 0.001; <i>E</i>-value 5.02), whereas PPIs and H2RAs showed no significant association. The association persisted across sensitivity analyses, including Western Pacific restriction, microbiome- and treatment-intensity adjustment, and PD-1/PD-L1 monotherapy. Comparator irAE associations were modest and heterogeneous.</p> Conclusions <p>Vonoprazan was associated with a phenotype-specific increase in cholangitis reporting among ICI-treated patients, a pattern absent with PPIs or H2RAs and unmatched across comparator irAEs. Prospective clinical validation is warranted.</p>

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Vonoprazan is associated with a phenotype-specific increase in cholangitis reporting in immune checkpoint inhibitor-treated patients: a VigiBase pharmacovigilance study

  • 期刊论文

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  • 发表日期：

    2026年6月26日

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  • Kazuyuki Mizuno,
  • Basile Chretien,
  • Kazuki Nishida,
  • Takanori Ito,
  • Hiroki Kawashima,
  • Yuichi Ando

摘要

Background

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), including cholangitis, a rare but clinically severe hepatobiliary phenotype. Whether potassium-competitive acid blockers (PCABs) such as vonoprazan are associated with hepatobiliary adverse-event reporting among ICI-treated patients remains unclear.

Methods

We performed a READUS-PV–compliant case–noncase disproportionality analysis using VigiBase, the WHO global individual case safety report database (inception through December 1, 2025; MedDRA v27.1). Adjusted reporting odds ratios (aRORs) were estimated for composite liver injury and a custom cholangitis-related endpoint for vonoprazan, proton pump inhibitors (PPIs), and histamine-2 receptor antagonists (H2RAs). The primary analysis was restricted to ICI-exposed reports and adjusted for age, sex, region, hepatotoxic co-medications, and ICI class. Sensitivity analyses addressed treatment intensity, microbiome-modifying co-medications, regional restriction, endpoint definition, sparse-data bias, and ICI subgroup. Six additional irAE categories were analyzed as comparator outcomes.

Results

Among 295,671 ICI-exposed reports, 1098 co-reported vonoprazan and 1186 reports met the cholangitis-related endpoint. Cholangitis was reported in 35 of 1098 vonoprazan-exposed reports (3.19%) versus 0.39% of ICI reports without vonoprazan. Vonoprazan was associated with increased cholangitis reporting (aROR 2.79; 95% CI 1.93–4.02; P < 0.001; E-value 5.02), whereas PPIs and H2RAs showed no significant association. The association persisted across sensitivity analyses, including Western Pacific restriction, microbiome- and treatment-intensity adjustment, and PD-1/PD-L1 monotherapy. Comparator irAE associations were modest and heterogeneous.

Conclusions

Vonoprazan was associated with a phenotype-specific increase in cholangitis reporting among ICI-treated patients, a pattern absent with PPIs or H2RAs and unmatched across comparator irAEs. Prospective clinical validation is warranted.