Bosentan
| Evidence Level: L4 | Predicted Indications: 8 |
Table of Contents
Bosentan: From Pulmonary Arterial Hypertension to Rheumatoid Arthritis
One-Sentence Summary
Bosentan is a dual endothelin receptor antagonist, originally used to treat pulmonary arterial hypertension and systemic sclerosis (scleroderma). The TxGNN model predicts it may be effective for Rheumatoid Arthritis, but so far this rests on 0 clinical trials and only preclinical (animal) studies as direct support, with most of the human literature addressing connective-tissue-disease-associated PAH rather than joint disease.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Pulmonary hypertension / pulmonary arterial hypertension, scleroderma, systemic sclerosis (the approved-indication text is not available in the India registration records) |
| Predicted New Indication | Rheumatoid arthritis |
| TxGNN Prediction Score | 0.9980 |
| Evidence Level | L4 |
| India Market Status | Listed in a compiled Indian medicine price dataset (9 of 9) – CDSCO approval status is not included in this data |
| Number of Listed Products | 9 (valid: 9) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. Based on known pharmacology, bosentan is a dual endothelin receptor antagonist (ET-A/ET-B). Endothelin signalling contributes to vascular dysfunction, synovial inflammation and cytokine release.
Its efficacy in pulmonary arterial hypertension and systemic sclerosis-related vasculopathy is established. Rheumatoid arthritis and these connective-tissue diseases share an inflammatory and vascular component, which may explain the model’s association. In mouse arthritis models, bosentan reduced joint inflammation, apparently through modulation of TNF-α and LTB4 (PMID 22249931, collagen-induced arthritis; PMID 18515326, zymosan-induced arthritis). Endothelin-1 levels are also reported to be raised in the plasma and synovium of RA patients.
The main caveat is that no human RA trial exists. Most human literature concerns PAH associated with connective tissue disease, not RA joint disease itself.
Other predicted indications are noted briefly:
- Gout, hypertrichosis, and several rare syndromes (brachydactyly-syndactyly, colobomatous microphthalmia-rhizomelic dysplasia, pseudoxanthoma elasticum forme fruste, kyphoscoliotic heart disease, elastoma): prediction-only signals with no trials and no plausible mechanistic support in the available data.
Clinical Trial Evidence
Currently no related clinical trials registered for rheumatoid arthritis.
Literature Evidence
Literature relevant to the predicted indication (rheumatoid arthritis):
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22249931 | 2012 | Preclinical (animal model) | Inflamm Res | Bosentan ameliorated collagen-induced arthritis in mice; TNF-α drives induction of endothelin system genes |
| 18515326 | 2008 | Preclinical (animal model) | J Leukoc Biol | Endothelins modulate inflammation in zymosan-induced arthritis, involving LTB4, TNF-α and CXCL-1 |
| 20054770 | 2009 | Case report | Kardiol Pol | Child with Eisenmenger syndrome treated with bosentan who was later diagnosed with juvenile rheumatoid arthritis; the case is a double diagnosis, not evidence of benefit in arthritis |
| 24268012 | 2014 | Review | Rheum Dis Clin North Am | PAH associated with connective tissue disease: poor prognosis, expanding treatment options |
| 16218473 | 2005 | Review | Lupus | PAH in connective tissue diseases, including (to a lesser extent) rheumatoid arthritis |
| 19487226 | 2009 | Review | Rheumatology (Oxford) | Vasculopathy and PAH in lupus, Sjögren’s syndrome and vasculitides |
| 21165350 | 2010 | Not classified | Can Respir J | Treatment of pulmonary hypertension in patients with connective tissue disease and interstitial lung disease |
| 18238768 | 2008 | Review | Am J Health Syst Pharm | Drug therapy options for complications of systemic sclerosis |
Several retrieved papers (for example, IL-17 and IL-15 hypernociception mouse studies) are not specific to bosentan and are omitted here.
India Market Information
Bosentan has 9 valid single-ingredient registrations, all oral tablets (strip of 10 tablets). The approved-indication text is not available in the registration records.
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| Registration No. 30538 | Bozetan 125mg Tablet | Strip of 10 tablets | Lupin Ltd |
| Registration No. 25886 | Bosentas 62.5 Tablet | Strip of 10 tablets | Cipla Ltd |
| Registration No. 31260 | Bosenat 125 Tablet | Strip of 10 tablets | Natco Pharma Ltd |
| Registration No. 121703 | Lupibose 62.5 Tablet | Strip of 10 tablets | Lupin Ltd |
| Registration No. 26128 | Bosentan 62.5 Tablet | Strip of 10 tablets | Care Formulation Labs Pvt Ltd |
Safety Considerations
- Disease-level contraindication signals (knowledge graph, not label text): liver failure, liver disease, drug-induced liver injury, hyperbilirubinemia (including hereditary forms and Gilbert syndrome), gallbladder disease, thrombocytopenia, anemia (including macrocytic anemia), congestive heart failure, pulmonary edema, and pulmonary veno-occlusive disease.
- Drug Interactions: 244 interactions are recorded in total. Examples at Moderate level include corticosteroids (hydrocortisone, dexamethasone, betamethasone, triamcinolone), antidiabetic agents (pioglitazone, canagliflozin, dapagliflozin, empagliflozin, chlorpropamide), clarithromycin, cimetidine, metronidazole, aprepitant, and cisapride. Corticosteroids and antidiabetic agents are commonly co-prescribed in RA populations, so this matters for the proposed use.
Please refer to the package insert for warnings and formal contraindications, as label text was not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The RA prediction has a high model score but no human trials and only mouse-model support, and the human literature concerns connective-tissue-disease PAH rather than RA. The liver, hematologic and heart-failure safety signals also need to be weighed against an uncertain benefit.
To proceed, the following is needed:
- Human clinical data in RA, starting with a proof-of-concept study or well-designed early-phase trial
- Mechanism of action data and a clearer mechanistic link to RA synovial disease
- Package insert warnings and contraindications from the India registration (currently a blocking gap for safety screening)
- Assessment of liver-function monitoring requirements and interactions with common RA co-medications
- Consideration of limited systemic sclerosis as a nearer-term research question, after verifying the digital-ulcer RCT evidence (such as RAPIDS), which was not included in the data compiled for this report
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.