Ketoconazole with Axitinib Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Axitinib
- Axitinib
- Inlyta®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Mar 04, 2024
Interaction Effect
Increased axitinib plasma concentrations
Interaction Summary
The concomitant use of axitinib (a CYP3A4/5 substrate) with ketoconazole (a strong CYP3A4 inhibitor[1]) should be avoided due to a risk of increased axitinib plasma concentrations [2]. In a drug interaction study of axitinib and ketoconazole, concomitant use in healthy subjects doubled the axitinib AUC and increased Cmax by 1.5 times [3]. When possible, an alternate concomitant medication with little or no CYP3A4/5 inhibitory effects should be substituted for ketoconazole. If concomitant use is required, reduce the dose of axitinib by approximately one-half and increase or decrease subsequent doses based on patient tolerability and safety. If ketoconazole is discontinued, wait 3 to 5 half-lives of ketoconazole and then return the axitinib dose to that used prior to ketoconazole initiation [2].
Severity
Major
Onset
Unspecified
Evidence
Established
How To Manage Interaction
The concomitant use of axitinib with a strong CYP3A4 inhibitor, such as ketoconazole[1], may cause increased axitinib plasma concentrations and should be avoided. When possible, substitute an alternate concomitant medication with little or no CYP3A4/5 inhibition. If concomitant use is required, reduce the dose of axitinib by approximately one-half and increase or decrease subsequent doses based on patient tolerability and safety. If ketoconazole is discontinued, wait 3 to 5 half-lives of ketoconazole and then return the axitinib dose to that used prior to ketoconazole initiation [2].
Mechanism Of Interaction
Inhibition of CYP3A-mediated axitinib metabolism by ketoconazole
Literature Reports
A) Concomitant therapy with ketoconazole significantly increased axitinib exposure in nonsmoking, healthy, adult volunteers (n=32) in a randomized, single-blind, two-way crossover study. Subjects received treatment A (single oral dose of axitinib 5 mg), followed by a 14-day washout, then treatment B (ketoconazole 400 mg/day orally on days 1 through 7 with a single dose of axitinib 5 mg orally on day 4), or treatment B, followed by a 14-day washout, then treatment A. The administration of axitinib with ketoconazole (n=28) compared with axitinib alone (n=31) showed significant increases in mean AUC (0 to infinity) 404.8 ng x hr/mL (95% CI, 332.3 to 493.2) vs 196.7 ng x hr/mL (95% CI, 162 to 238.8); geometric mean ratio, 2.06 (90% CI, 1.84 to 2.3). Likewise, significant increases were seen in the AUC (0 to time of last quantifiable concentration) 401.9 ng x hr/mL (95% CI, 330.1 to 489.3) vs 193.8 ng x hr/mL (95% CI, 159.9 to 234.9); geometric mean ratio, 2.07 (90% CI, 1.86 to 2.31), and Cmax 76.7 ng/mL (95% CI, 65.6 to 89.7) vs 51 ng/mL (95% CI, 43.9 to 59.3); geometric mean ratio 1.5 (90% CI, 1.33 to 1.7). The administration of axitinib with ketoconazole compared with axitinib alone also increased the mean plasma t(1/2) for axitinib from 9.44 hours +/- 9.98 hours to 13.1 hours +/- 8.85 hours and increased Tmax from 1.5 hours (range, 1 to 3 hours) to 2 hours (range, 1 to 4.13 hours). Changes from baseline in blood pressure were minimal and similar with axitinib alone and in combination with ketoconazole. Treatment-related adverse events with concomitant therapy were generally mild and consisted of headache, nausea, dizziness, loose stools, and vomiting [3].
References
1 ) Product Information: ketoconazole oral tablets, ketoconazole oral tablets. Apotex,Corp, Weston, FL, 2004.
2 ) Product Information: INLYTA(R) oral tablets, axitinib oral tablets. Pfizer Inc. (per FDA), New York, NY, 2012.
3 ) Pithavala YK, Tong W, Mount J, et al: Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs 2012; 30(1):273-281.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
Ketoconazole Overview
-
Ketoconazole is used to treat fungal infections when other medications are not available or cannot be tolerated. Ketoconazole should not be used to treat fungal meningitis (infection of the membranes surrounding the brain and spinal cord caused by a fungus) or fungal nail infections. Ketoconazole is in a class of antifungals called imidazoles. It works by slowing the growth of fungi that cause infection.
Axitinib Overview
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Axitinib is used alone to treat advanced renal cell carcinoma (RCC, a type of cancer that begins in the cells of the kidneys) in people who have not been treated successfully with another medication. Axitinib is used in combination with avelumab (Bavencio) or pembrolizumab (Keytruda) to treat advanced renal cell carcinoma. Axitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.
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Definitions
Severity Categories
Contraindicated
These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.
Major
This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.
Moderate
This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.
Minor
While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.
Onset
Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.
Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.
Evidence
Level of documentation of the interaction.
Established: The interaction is documented and substantiated in peer-reviewed medical literature.
Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.
How To Manage The Interaction
Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.
It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.
Mechanism Of Interaction
The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.
Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.
Where Does Our Information Come From?
Information for our drug interactions is compiled from several drug compendia, including:
The prescribing information for each drug, as published on DailyMED, is also used.
Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.
The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.