Ketoconazole with Saquinavir Interaction Details
Brand Names Associated with Ketoconazole
- Ketoconazole
- Nizoral®
Brand Names Associated with Saquinavir
- Invirase®
- Saquinavir
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Dec 02, 2023
Interaction Effect
Increased saquinavir plasma concentrations and increased risk of QT interval prolongation
Interaction Summary
Both ketoconazole and saquinavir are CYP3A4 substrates and inhibitors. Exposure to one or both agents may be increased with concomitant use. Oral ketoconazole has been shown to independently prolong the QT interval Saquinavir has also been shown to prolong the QT interval in a dose-dependent manner. Coadministration of saquinavir/ritonavir with agents such as ketoconazole that can increase saquinavir exposure and are known to prolong the QT interval is contraindicated. If no alternative therapy is available and benefits outweigh the risks of concomitant use, limit the ketoconazole dose to 200 mg/day and perform an ECG prior to therapy initiation. Do not initiate concomitant therapy in patients with a QT interval greater than 450 msec, otherwise perform an on-treatment ECG after 3 to 4 days of therapy. If the QT interval is greater than 480 msec or has increased by more than 20 msec from baseline, consider discontinuing one or both agents .
Severity
Contraindicated
Onset
Unspecified
Evidence
Established
How To Manage Interaction
Coadministration of saquinavir/ritonavir (CYP3A4 substrate/inhibitor) with agents such as ketoconazole (CYP3A4 inhibitor/substrate) that can increase saquinavir exposure and are known to prolong the QT interval is contraindicated. Plasma concentrations of ketoconazole may also be elevated by CYP3A4-mediated enzyme inhibition by saquinavir. If no alternative therapy is available and benefits outweigh the risks of concomitant use, limit the ketoconazole dose to 200 mg/day and perform an ECG prior to therapy initiation. Do not initiate concomitant therapy in patients with a QT interval greater than 450 msec, otherwise perform an on-treatment ECG after 3 to 4 days of therapy. If the QT interval is greater than 480 msec or has increased by more than 20 msec from baseline, consider discontinuing one or both agents.
Mechanism Of Interaction
Inhibition of CYP3A-mediated metabolism of saquinavir by ketoconazole; additive effects on QT interval prolongation
Literature Reports
A) Oral ketoconazole dosed at 200 mg twice daily for 3 to 7 days resulted in mean maximum increases of the QT interval of about 6 to 12 msec at 1 to 4 hours after ketoconazole administration .
B) Following concurrent administration of oral saquinavir 1000 mg/ritonavir 100 mg twice daily with oral ketoconazole 200 mg/day in 12 healthy volunteers, the geometric mean AUC and Cmax of ketoconazole increased by 168% (90% confidence interval (CI), 146% to 193%) and 45% (90% CI, 32% to 59%), respectively .
C) A study involving 7 HIV-infected men investigated the effect of ketoconazole on the plasma concentrations of saquinavir. Patients received saquinavir 600 mg 3 times daily with meals along with 2 other antiretroviral medications. Seven days later, ketoconazole 200 mg/day was added for 1 week and then increased to 400 mg/day for 1 week. Saquinavir plasma concentrations were measured and there were no significant differences between any 2 of the 3 trough (p=0.39, p=0.53, and p=0.8) or peak (p=0.69, p=0.88, and p=0.98) measurements. There were, however, significant differences in the mean saquinavir values between the trough and peak measurements before ketoconazole, after 200 mg/day, and after 400 mg/day of ketoconazole (p=0.015, p=0.019, and p=0.022). The results indicate that ketoconazole does not consistently increase the saquinavir concentrations at the doses administered in this study. Intersubject variability is significant in both peak and trough levels .
D) A pharmacokinetic study involving 12 HIV-positive patients treated with ritonavir, saquinavir, and ketoconazole determined that ketoconazole may inhibit the systemic clearance of saquinavir. The patients were receiving 400 mg each of ritonavir and saquinavir twice daily when ketoconazole 200 mg or 400 mg once a day for 10 days was added to their medication treatment. Blood and cerebrospinal fluid (CSF) samples were taken before and after the addition of ketoconazole. The AUC, plasma concentration 12 hours after the dose, and half-life of saquinavir were significantly increased (37%, 94%, and 38%, respectively) by concomitant ketoconazole administration. Ketoconazole did not significantly affect (p greater than 0.06) the CSF pharmacokinetics of saquinavir .
Ketoconazole Overview
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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.
Saquinavir Overview
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Saquinavir is used in combination with ritonavir (Norvir) and other medications to treat human immunodeficiency virus (HIV) infection. Saquinavir is in a class of medications called protease inhibitors. It works by decreasing the amount of HIV in the blood. Although saquinavir does not cure HIV, it may decrease your chance of developing acquired immunodeficiency syndrome (AIDS) and HIV-related illnesses such as serious infections or cancer. Taking these medications along with practicing safer sex and making other lifestyle changes may decrease the risk of transmitting the HIV virus to other people.
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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.