Ketoconazole
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Ketoconazole: From Superficial Fungal Infections to Acne
One-Sentence Summary
Ketoconazole is an azole antifungal, originally used for skin and mucosal fungal infections such as tinea, seborrhoeic dermatitis, pityriasis versicolor and candidiasis. The TxGNN model predicts it may be effective for acne (disease), with 1 clinical trial (small, non-phased, still active, no results) and mostly indirect literature supporting this direction. Among the other predictions for this drug, vulvovaginal candidiasis has much stronger support (2 Phase 3 trials) and is discussed in the conclusion.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Superficial fungal infections and related skin conditions (tinea pedis, tinea corporis, seborrhoeic dermatitis, pityriasis versicolor, cutaneous and oral candidiasis, and others). The approved indication text is not available in the Singapore registration records. |
| Predicted New Indication | Acne (disease) |
| TxGNN Prediction Score | 99.80% |
| Evidence Level | L4 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 20 |
| Recommended Decision | Hold (treat as a research question) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Ketoconazole is a well-known azole antifungal. Azoles inhibit fungal lanosterol 14-alpha-demethylase (CYP51), which blocks ergosterol synthesis and disrupts the fungal cell membrane. This is the basis of its use in tinea, candidiasis and seborrhoeic dermatitis.
Two plausible but indirect links to acne are described:
- Antimicrobial and anti-lipase effects. Malassezia (Pityrosporum) yeasts can contribute to follicular inflammation, and Pityrosporum folliculitis is often misdiagnosed as acne vulgaris. Laboratory studies also report that ketoconazole inhibits the growth and lipase activity of Propionibacterium acnes, which could matter given rising antibiotic resistance.
- Steroidogenesis inhibition. Ketoconazole inhibits CYP17A1 and lowers androgen levels, which are relevant to acne.
Both links remain mechanistic or in vitro. Clinical confirmation is limited to one small ongoing trial.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT07237763 | Not applicable | Active, not recruiting | 52 | Randomised comparison of topical ketoconazole 2% cream vs topical adapalene 2% cream in mild comedonal and papulopustular acne (12 weeks). Aims to determine whether ketoconazole can be an alternative to retinoids with fewer side effects. No results available. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 28111792 | 2017 | In vitro | Microbiol Immunol | Ketoconazole inhibits P. acnes lipase activity and growth, suggesting a possible alternative to antibiotics. |
| 20045949 | 2010 | In vitro | Biol Pharm Bull | In vitro activity of azole antifungals against P. acnes isolates from acne patients. |
| 12566804 | 2003 | Review | Dermatology | Overview of systemic acne treatment; antibiotics are the agents of choice for papulopustular acne. |
| 32872149 | 2020 | Review | Pharmaceuticals (Basel) | Review of adapalene, the comparator in the ongoing trial. |
| 8593718 | 1995 | Clinical series | Clin Exp Dermatol | Pityrosporum folliculitis is frequently misdiagnosed as acne vulgaris; therapeutic trials in 62 patients. |
| 8629828 | 1996 | Case report | Arch Dermatol | Association between neonatal papulopustular eruptions and Malassezia furfur infection. |
| 8255067 | 1993 | Review | Keio J Med | Pityrosporum ovale as an opportunistic pathogen in several skin diseases. |
Much of the remaining retrieved literature is tangential (polycystic ovary syndrome, Cushing's syndrome, neonatal rashes) and is not evidence for ketoconazole in acne.
Singapore Market Information
There are 20 valid registrations, all single-ingredient products. Approved indication text is not available in the registration records. Main authorisations:
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN01117P | NIZORAL CREAM 2% (Janssen) | Cream | Not available |
| SIN04926P | NIZORAL SHAMPOO 20 mg/g | Shampoo | Not available |
| SIN04863P | PHYTORAL TABLET 200 mg | Tablet | Not available |
| SIN10955P | KETOCONAZOLE TABLETS 200 mg (Hovid) | Tablet | Not available |
| SIN10030P | PHYTORAL OINTMENT 2% w/w | Ointment | Not available |
Available forms include creams, shampoos, ointments and 200 mg tablets. A topical cream is therefore already available for the route used in the acne trial.
Safety Considerations
- Contraindication-related conditions (from a knowledge graph, not label text): long QT syndrome, torsades de pointes, liver disease, gallbladder disease, adrenocortical insufficiency, Addison disease, skin atrophy, telangiectasia, peripheral vascular disease, and achlorhydria.
- Drug interactions: 100 interactions were identified. Major-level examples include loperamide, triamcinolone and budesonide. Moderate-level examples include famotidine, ranitidine, omeprazole, rabeprazole, hydrocortisone, dexamethasone, betamethasone, pioglitazone, aprepitant and alosetron. Acid-reducing drugs matter because oral ketoconazole needs gastric acidity for absorption. Systemic ketoconazole is also known for hepatotoxicity and CYP3A4 interactions, so a topical route is preferable for any acne use.
Please refer to the package insert for label warnings and contraindications, which were not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The acne prediction score is very high (99.80%), but the evidence is L4. There is one small, non-phased trial (n=52) with no results, and the supporting data are in vitro or indirect. This is a research question, not a ready-to-use repurposing candidate. For comparison, the vulvovaginal candidiasis prediction is rated L1 (Proceed with Guardrails). It has two Phase 3 trials, and it extends the established antifungal mechanism to a vaginal formulation.
To proceed, the following is needed:
- Results of NCT07237763, and larger randomised trials with defined acne endpoints
- Head-to-head or add-on comparison against standard acne therapies
- Package insert warnings and contraindications from HSA
- A formal mechanism of action record (from DrugBank)
- For any vulvovaginal candidiasis follow-up: confirm the ketoconazole arm of NCT01293643, and use topical or vaginal routes with attention to non-albicans Candida resistance
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.