Ketoconazole and atorvastatin
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Ketoconazole + Atorvastatin: Drug Interaction
Mechanism
Atorvastatin is primarily metabolized by CYP3A4. Ketoconazole is a potent inhibitor of CYP3A4 (and to a lesser extent CYP2C9 and other CYPs). When co-administered, ketoconazole inhibits the hepatic metabolism of atorvastatin, causing its plasma levels to rise significantly.
- Katzung's Basic and Clinical Pharmacology (16th ed.) states: "The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include... ketoconazole and its congeners..."
Clinical Consequence
Elevated plasma atorvastatin concentrations increase the risk of statin toxicity, principally:
- Myopathy / Rhabdomyolysis - The most serious risk. Elevated statin levels cause skeletal muscle damage, which can progress to rhabdomyolysis with myoglobinuria and renal injury. Minor CK elevations are common; severe elevations signal impending rhabdomyolysis.
- Hepatotoxicity - Raised statin levels increase the risk of transaminase elevation and hepatic injury. Both ketoconazole (itself hepatotoxic) and atorvastatin carry hepatotoxic potential.
The drug interaction table in Katzung explicitly lists: "HMG-CoA reductase inhibitors: [P] Decreased metabolism of lovastatin, simvastatin, and, to a lesser extent, atorvastatin" - note that atorvastatin is somewhat less susceptible than lovastatin/simvastatin because it has alternate metabolic pathways, but the interaction is still clinically significant.
Which Statins Are Most vs. Least Affected?
| Statin | CYP pathway | Risk with ketoconazole |
|---|---|---|
| Lovastatin, Simvastatin | CYP3A4 (primary) | Highest - contraindicated |
| Atorvastatin | CYP3A4 (primary) | High - avoid or reduce dose |
| Fluvastatin, Rosuvastatin | CYP2C9 (primary) | Also inhibited by ketoconazole (CYP2C9 inhibitor) |
| Pravastatin | Non-CYP (sulfation) | Lowest risk - preferred alternative |
The Textbook of Family Medicine (9th ed.) explicitly states: "The coadministration of drugs or compounds that inhibit cytochrome P450 3A4 (azole-type antifungals [ketoconazole, itraconazole]...) with atorvastatin, simvastatin, and lovastatin is contraindicated."
Katzung further recommends: "Pravastatin and rosuvastatin appear to be the statins of choice for use with... the ketoconazole group of antifungal agents."
Additional Interaction: P-glycoprotein
Ketoconazole is also a P-glycoprotein inhibitor. Atorvastatin is a P-gp substrate, so ketoconazole can additionally reduce atorvastatin's efflux, further increasing its bioavailability and plasma exposure. (Goodman & Gilman's notes this mechanism in the context of drugs like ketoconazole and atorvastatin increasing aliskiren levels via the same P-gp inhibition pathway.)
Clinical Management
- Avoid concurrent use of ketoconazole with atorvastatin (or simvastatin/lovastatin) where possible - considered contraindicated by many guidelines.
- If an azole antifungal is necessary alongside statin therapy, switch to pravastatin (non-CYP metabolized) or use a topical/less systemically absorbed azole.
- If the combination cannot be avoided: use the lowest effective dose of atorvastatin, monitor for muscle pain, weakness, and liver enzymes closely, and check CK if symptoms arise.
- Instruct patients to report muscle pain, tenderness, or dark urine (myoglobinuria) immediately.
Sources:
- Katzung's Basic and Clinical Pharmacology, 16th ed. - Toxicity section (statins), p. 992; Azole drug interactions table
- Textbook of Family Medicine, 9th ed. - Statins section
- Goodman & Gilman's The Pharmacological Basis of Therapeutics - Drug-Drug Interactions
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