Ketoconazole
| Evidence Level: L4 | Predicted Indications: 1 |
Table of Contents
Ketoconazole: Acne (disease)
One-Sentence Summary
Ketoconazole is an azole antifungal originally used for skin and mucosal fungal infections (such as tinea, seborrheic dermatitis, and candidiasis) and for some systemic fungal infections (such as histoplasmosis and aspergillosis). The TxGNN model predicts it may be effective for acne, but support is still early: 1 clinical trial (a small, non-Phase 2/3 study) and 14 publications, mostly reviews, case reports, and laboratory studies.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Acne (disease) |
| TxGNN Prediction Score | 0.9980 |
| Evidence Level | L4 |
| Canada Market Status | Marketed (marketed DINs: 4 of 4) |
| Number of DINs | 4 (marketed: 4) |
| Recommended Decision | Hold (research question; if pursued, topical use only) |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. The reasoning below is therefore based on general pharmacological knowledge, not on supplied MOA data.
Ketoconazole inhibits fungal CYP51 (lanosterol 14α-demethylase), which gives it its antifungal activity. This includes activity against Malassezia (Pityrosporum) yeasts. These yeasts are linked to follicular and pustular eruptions that can look like acne. One report describes neonatal Malassezia pustulosis, and another describes Pityrosporum folliculitis, which is often misdiagnosed as acne vulgaris. Some of the benefit seen in “acne-like” conditions may therefore come from treating a fungal cause.
There are two further plausible routes. At higher systemic doses, ketoconazole inhibits steroidogenic enzymes such as CYP17A1 and lowers androgen synthesis. That fits the literature on hyperandrogenic skin manifestations (including acne) in polycystic ovary syndrome. Laboratory studies also show that ketoconazole inhibits the growth and lipase activity of Propionibacterium acnes (Cutibacterium acnes), the bacterium involved in acne inflammation. Topical use may add mild anti-inflammatory activity.
The high TxGNN score is a computational prediction only. The systemic antiandrogen route is unfavourable because of serious safety risks (see Safety Considerations), so any realistic repurposing path would be topical.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT07237763 | NA | Active, not recruiting | 52 | Randomized comparison of topical ketoconazole 2% cream versus topical adapalene 2% cream in mild comedonal and papulopustular acne, over 12 weeks. It aims to see whether ketoconazole could replace a topical retinoid with fewer side effects and better compliance. No results are available yet. |
This single small trial supports only exploratory interest. It does not meet the criteria for a Phase 2/3 RCT.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 28111792 | 2017 | Laboratory study | Microbiol Immunol | Ketoconazole inhibits P. acnes lipase activity and growth, suggesting a possible alternative to antibiotics, given rising resistance. |
| 20045949 | 2010 | Laboratory study | Biol Pharm Bull | In vitro activity of azole antifungals, including ketoconazole, against P. acnes isolated from acne patients. |
| 12566804 | 2003 | Review | Dermatology | Overview of systemic acne treatments (antibiotics, hormonal agents, and others). |
| 8255067 | 1993 | Review | Keio J Med | Pityrosporum ovale is associated with pityriasis versicolor, folliculitis, and seborrheic dermatitis. |
| 8593718 | 1995 | Clinical study | Clin Exp Dermatol | In 62 patients, Pityrosporum folliculitis was frequently misdiagnosed as acne vulgaris; diagnosis and therapeutic trials are described. |
| 8629828 | 1996 | Case report | Arch Dermatol | Neonatal papulopustular facial eruptions, often called neonatal acne, may be associated with Malassezia furfur infection. |
| 8090657 | 1993 | Review | Pol Tyg Lek | Treatment of hyperandrogenic manifestations in PCOS, including acne and seborrhea. |
| 19445767 | 2009 | Review | BMJ Clin Evid | PCOS overview; acne is one of its associated features. |
| 23600337 | 2013 | Review | FP Essentials | Common infant skin rashes, including neonatal and infantile acne. |
| 32872149 | 2020 | Review | Pharmaceuticals (Basel) | Adapalene, the comparator in the trial, as a first-line acne treatment. |
The remaining retrieved papers (a free-clinic dermatologic formulary study, a confluent and reticulated papillomatosis case, and three Cushing’s syndrome case reports) are only loosely related to this prediction and are not listed.
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02245662 | KETODERM CREAM 2% | Cream (from product name) | Not listed in the compiled data |
| 02231061 | TEVA-KETOCONAZOLE | Not listed | Not listed in the compiled data |
| 02237235 | APO-KETOCONAZOLE | Not listed | Not listed in the compiled data |
| 02182920 | NIZORAL | Not listed | Not listed in the compiled data |
All four are valid single-ingredient authorizations.
Safety Considerations
Package insert warnings and contraindications were not available in the data compiled for this report. Please refer to the Health Canada package insert for these. The following comes from the knowledge graph and drug-interaction data.
- Conditions flagged as contraindicated (knowledge graph, not label text): long QT syndrome (including familial), torsades de pointes, liver disease, gallbladder disease, adrenocortical insufficiency, Addison disease, skin atrophy, telangiectasis and other capillary disease, hereditary hemorrhagic telangiectasia, peripheral vascular and arterial disease, intermittent claudication, and achlorhydria.
- Systemic-use concerns: the repurposing analysis highlights hepatotoxicity risk (boxed warning), adrenal insufficiency, QT prolongation, and extensive CYP3A4-mediated interactions. These make systemic use for acne unfavourable.
- Drug interactions: 100 interactions were identified. The main ones in the first 20 reviewed are:
- Major: loperamide, triamcinolone, budesonide.
- Moderate: famotidine, ranitidine, omeprazole, rabeprazole (acid-reducing agents), hydrocortisone, dexamethasone, betamethasone, pioglitazone, alosetron, aprepitant, atropine, hyoscyamine, methscopolamine, bisacodyl.
- Minor: amphotericin B (including the lipid complex).
Conclusion and Next Steps
Decision: Hold
Rationale: The evidence is at L4: a model prediction backed by laboratory and mechanistic data and a single small, non-Phase 2/3 trial with no results. The systemic route carries significant safety risks, so only a topical path is realistic. The package insert safety data needed for a safety screening is also missing.
To proceed, the following is needed:
- Results from NCT07237763, and ideally a larger randomized trial of topical ketoconazole in acne
- Package insert warnings and contraindications from Health Canada
- Mechanism-of-action data from DrugBank
- Dosage form and approved indication details for each DIN, to confirm topical product availability
- Evidence separating any benefit from Malassezia folliculitis (a fungal mimic of acne) from benefit in true acne vulgaris
- A safety plan if systemic use is ever considered (liver function, adrenal function, ECG/QT monitoring, and interaction management)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.