Abstract
High-dose ketoconazole (400 mg q.d. for ≥5 days) has been the gold-standard strong cytochrome P450 3A (CYP3A) inhibitor in drug development drug-drug interaction (DDI) studies. In 2013, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) advised against using this ketoconazole regimen following review of clinical safety reports. We systematically evaluated 19 strong CYP3A inhibitors from regulatory guidances and a literature database to identify itraconazole (200 mg b.i.d. on day 1, q.d. on days 2-6) and clarithromycin (500 mg b.i.d. for 7 days) as acceptable ketoconazole alternatives.
MeSH terms
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Clarithromycin / administration & dosage
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Clarithromycin / pharmacology*
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors*
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Databases, Factual
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Drug Design
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Drug Interactions
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / pharmacology
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Europe
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Humans
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Itraconazole / administration & dosage
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Itraconazole / pharmacology*
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Ketoconazole / administration & dosage
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Ketoconazole / adverse effects
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Ketoconazole / pharmacology*
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United States
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United States Food and Drug Administration
Substances
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Cytochrome P-450 CYP3A Inhibitors
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Enzyme Inhibitors
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Itraconazole
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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Clarithromycin
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Ketoconazole