Bosentan
| Evidence Level: L4 | Predicted Indications: 8 |
Table of Contents
Bosentan: endothelin receptor antagonist → rheumatoid arthritis
One-Sentence Summary
Bosentan is a dual endothelin receptor antagonist (ET-A/ET-B) used in pulmonary arterial hypertension and related connective tissue conditions. The TxGNN model predicts it may be effective for rheumatoid arthritis. No clinical trials are registered for this use, and the supporting literature consists mainly of reviews and animal-model studies, so the evidence is preclinical and indirect only.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | rheumatoid arthritis |
| TxGNN Prediction Score | 0.9980 |
| Evidence Level | L4 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Bosentan is known as a dual endothelin receptor antagonist (ET-A and ET-B), blocking the effects of endothelin-1.
Endothelin-1 is implicated in synovial inflammation, vasculopathy and fibrosis. In a collagen-induced arthritis mouse model, bosentan reduced disease severity, with a proposed role for TNF-α in inducing endothelin system genes. A separate mouse study found that endothelins modulate the inflammatory reaction in zymosan-induced arthritis through LTB4, TNF-α and CXCL-1. Bosentan’s use in connective-tissue-disease-associated pulmonary hypertension gives an indirect link to rheumatic disease.
These findings are mechanistic and preclinical. No human trial of bosentan for the joint disease of rheumatoid arthritis was identified, so the prediction remains a research question.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22249931 | 2012 | Preclinical (mouse model) | Inflammation Research | Bosentan ameliorated collagen-induced arthritis in mice; TNF-α implicated in inducing endothelin system genes |
| 18515326 | 2008 | Preclinical (mouse model) | Journal of Leukocyte Biology | Endothelins modulate inflammation in zymosan-induced arthritis via LTB4, TNF-α and CXCL-1 |
| 24268012 | 2014 | Review | Rheumatic Diseases Clinics of North America | Pulmonary arterial hypertension related to connective tissue disease: significant morbidity, poor prognosis |
| 16218473 | 2005 | Review | Lupus | PAH as a complication of connective tissue diseases, less often rheumatoid arthritis |
| 18238768 | 2008 | Review | Am J Health-Syst Pharm | Drug therapy options for complications of systemic sclerosis |
| 19487226 | 2009 | Review | Rheumatology (Oxford) | Vasculopathy and PAH in connective tissue disease and vasculitis |
| 20054770 | 2009 | Case report | Kardiologia Polska | Child with Eisenmenger syndrome on bosentan who was later diagnosed with juvenile rheumatoid arthritis; the report does not assess bosentan for arthritis |
| 16766656 | 2006 | Preclinical (not bosentan-specific) | PNAS | IL-15-induced hypernociception in mice is mediated by endothelin; relevant to arthritis pain mechanisms |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 12134P | Bosentan RBX | Tablet 62.5 mg (as monohydrate) | Not recorded in the local data |
Safety Considerations
Label-based warnings and contraindications are not available in the data compiled for this report. Please refer to the TGA-approved Product Information (PI) for safety information.
Drug interactions: 100 interactions were recorded. Those listed are all of moderate severity, including:
- Corticosteroids: hydrocortisone, triamcinolone, dexamethasone, betamethasone
- Antidiabetic agents: pioglitazone, acetohexamide, chlorpropamide, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
- Anti-infectives: metronidazole, clarithromycin, clotrimazole
- Others: aprepitant, cimetidine, cisapride, dronabinol, eliglustat, eluxadoline
Corticosteroids are commonly used in rheumatoid arthritis, so this interaction group is relevant to any future study.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction score is high, but no clinical trial studies bosentan in rheumatoid arthritis. The supporting evidence is limited to mouse models and indirect reviews of connective-tissue-related pulmonary hypertension. Although the literature includes animal studies of bosentan in arthritis, no study in patients with the disease was identified, and the evidence is best viewed as hypothesis-generating.
To proceed, the following is needed:
- Mechanism of action data to support the mechanistic-link analysis
- TGA Product Information warnings and contraindications for a safety review
- Human proof-of-concept data (for example, a small phase 2 trial in rheumatoid arthritis, with attention to liver function monitoring and interactions with usual rheumatoid arthritis therapies)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.