Ritonavir
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Ritonavir: From HIV/AIDS and Hepatitis C to Simian Immunodeficiency Virus Infection
One-Sentence Summary
Ritonavir is an HIV protease inhibitor and pharmacokinetic booster, originally used to treat HIV/AIDS and chronic hepatitis C (as part of combination regimens). The TxGNN model's top-ranked prediction is simian immunodeficiency virus (SIV) infection, a primate model of HIV. There are no clinical trials and 11 publications (all preclinical or laboratory-based) supporting this prediction, so it has little direct clinical repurposing value.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Chronic hepatitis C virus infection, HIV infection / AIDS (from the knowledge graph; Singapore label text not available) |
| Predicted New Indication | Simian immunodeficiency virus infection |
| TxGNN Prediction Score | 99.92% |
| Evidence Level | L4 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 4 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available. Based on known information, ritonavir is an HIV protease inhibitor and a CYP3A4 inhibitor used to boost other protease inhibitors, and its efficacy in HIV infection is established. Mechanistically, it may be applicable to SIV.
SIV is a lentivirus closely related to HIV, and its protease is inhibited by HIV protease inhibitors, though susceptibility varies. A laboratory study found ritonavir inhibited SIVmac239 with a 50% effective concentration of about 13 nM, compared with about 25 nM for HIV-1. Macaque studies of combination antiretroviral therapy also support biological plausibility.
However, SIV infection is an animal model of the disease ritonavir already treats. This is best read as a preclinical validation of the existing HIV indication, not a new human indication. The model's other top predictions (feline AIDS, a genetic neurodevelopmental disorder) have no supporting evidence and are likely graph-based artefacts.
Clinical Trial Evidence
Currently no related clinical trials registered for SIV infection.
For context, the other predicted indications with clinical trial data are summarised below:
| Predicted Indication | Evidence | Interpretation |
|---|---|---|
| Congenital HIV | 1 Phase 3 randomized trial (NCT00102960, n=377, completed) of antiretroviral strategies in infants | Extension of the existing HIV indication to a specific population; the trial compares strategies, not ritonavir alone |
| Hepatitis B virus infection | 10 trials, mostly small, open-label, PK or DDI studies where ritonavir acts as a booster (e.g. NCT03638076, Phase 2, n=20) | No intrinsic anti-HBV activity established |
| AIDS related complex | 3 trials, including a pilot HAART study (NCT00001075, n=55) | On-label HIV use, not true repurposing |
| Hepatitis A virus infection | Many HCV/HIV trials of ritonavir-boosted regimens | Not HAV studies; association likely driven by the shared "hepatitis" label |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12709355 | 2003 | In vitro | Antimicrob Agents Chemother | SIVmac239 inhibited by ritonavir (EC50 ~13 nM), comparable to HIV-1 (~25 nM) |
| 15040537 | 2004 | In vitro | Antivir Ther | Activity of approved anti-HIV drugs against HIV-2, SIV and SHIV strains |
| 16973590 | 2006 | Animal study (macaque) | J Virol | Rapid viral decay in SIV-infected macaques on quadruple antiretroviral therapy |
| 22737073 | 2012 | Animal study (macaque) | PLoS Pathog | Highly intensified ART gave long-term viral suppression in a simian AIDS model |
| 34903055 | 2021 | Animal study | mBio | Lentiviral infection persists in brain despite effective ART |
| 25033210 | 2014 | Animal study | PLoS One | cART plus the HDAC inhibitor SAHA in SIV-infected rhesus macaques |
| 12951220 | 2003 | Animal study | J Virol Methods | AZT, 3TC and lopinavir/ritonavir effects on the CD8 subset in SHIV-infected monkeys |
| 17350308 | 2007 | Animal model development | Microbes Infect | A novel SHIV with HIV-1 protease as a tool for testing protease inhibitors in macaques |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14288P | Norvir Tablets 100 mg | Film-coated tablet | Not available |
| SIN16877P | Paxlovid Film-Coated Tablets | Film-coated tablet | Not available |
| SIN13250P | Kaletra Tablet 200mg/50mg | Film-coated tablet | Not available |
| SIN11492P | Kaletra Oral Solution | Syrup | Not available |
Safety Considerations
- Contraindications flagged in the knowledge graph (not label text): long QT syndrome and torsades de pointes, other cardiac conduction disorders (AV block, sudden cardiac arrest), coronary artery disease and cardiomyopathy, pancreatitis, liver disease and cirrhosis, gallbladder disease, diabetes and hyperglycaemia (including diabetic ketoacidosis), hypertriglyceridaemia and familial hyperlipidaemia, hyperbilirubinaemia (including Gilbert syndrome), gout, potassium deficiency, chronic hepatitis B and haemophilia.
- Drug interactions: 100 interactions were identified. Major-level interactions in the data include loperamide, triamcinolone and budesonide. Moderate-level ones include metformin and other antidiabetics, other corticosteroids (hydrocortisone, dexamethasone, betamethasone), clarithromycin, metronidazole, bupropion, aprepitant, alosetron and lorcaserin. Ritonavir is a strong CYP3A4 inhibitor, so interaction screening is essential.
- Population-specific signals from the literature: adrenal dysfunction in infants exposed to lopinavir/ritonavir, and birth-defect surveillance in pregnancy.
Please refer to the package insert for full warnings, as label text was not available for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The SIV prediction rests on laboratory and macaque studies only, with no human trials. SIV is an animal model of HIV, which ritonavir already treats, so it offers no new clinical indication. The other high-scoring predictions are either on-label HIV uses, indirect evidence from ritonavir used as a booster, or unsupported artefacts. The one possible lead is hepatitis E virus infection (L4, in vitro only: ritonavir blocked viral internalization and cleared virus with ribavirin), which would be worth a separate research question.
To proceed, the following is needed:
- Singapore package insert warnings and contraindications (HSA)
- Mechanism of action data (DrugBank)
- For any human indication of interest (e.g. hepatitis E), controlled clinical data and a DDI plan for immunosuppressed and transplant patients
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.