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Drug Interactions between amprenavir and sirolimus protein-bound

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

amprenavir sirolimus protein-bound

Applies to: amprenavir and sirolimus protein-bound

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with potent inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may significantly increase the systemic exposure to sirolimus, which is a known substrate for both the isoenzyme and efflux transporter. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. However, significant increases in systemic exposure have been reported for oral sirolimus coadministered with potent inhibitors of CYP450 3A4 and/or P-gp such as azole antifungal agents and protease inhibitors. When a single 5 mg dose of sirolimus was administered with the potent dual CYP450 3A4/P-gp inhibitor ketoconazole (200 mg/day orally for 10 days) in healthy study subjects, mean sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 4- and 11-fold, respectively. Likewise, the potent CYP450 3A4 inhibitor posaconazole (400 mg oral suspension twice a day for 16 days) increased mean Cmax and AUC of a single 2 mg dose of sirolimus by nearly 7- and 9-fold, respectively, while the potent CYP450 3A4 inhibitor voriconazole (400 mg orally every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the same values by 7- and 11-fold, respectively. The dual CYP450 3A4/P-gp inhibitor, boceprevir (800 mg three times a day for 11 days), increased the Cmax and AUC of a single 2 mg dose of sirolimus by 10- and 17-fold, respectively. Another dual CYP450 3A4/P-gp inhibitor, telaprevir (1125 mg every 12 hours), increased the dose-normalized Cmax and AUC of sirolimus in ten liver transplant patients by 3- and 26-fold, respectively. Increased exposures to sirolimus may increase the risk of adverse effects such as stomatitis, nausea, diarrhea, vomiting, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, edema, rash, alopecia, and hemorrhage.

MANAGEMENT: Concomitant use of protein-bound sirolimus with potent CYP450 3A4 and/or P-gp inhibitors should generally be avoided.

References (12)
  1. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  2. (2001) "Product Information. Rapamune (sirolimus)." Wyeth-Ayerst Laboratories
  3. Claesson K, Brattstrom C, Burke JT (2001) "Sirolimus and erythromycin interaction: two cases." Transplant Proc, 33, p. 2136
  4. Floren LC, Christians U, Zimmerman JJ, et al. (1999) "Sirolimus oral bioavailability increases ten-fold with concomitant ketoconazole." Clin Pharmacol Ther, 65, p. 159
  5. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
  6. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  7. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  8. Cerner Multum, Inc. "Australian Product Information."
  9. Dodds-Ashley E (2010) "Management of drug and food interactions with azole antifungal agents in transplant recipients." Pharmacotherapy, 30, p. 842-54
  10. (2011) "Product Information. Victrelis (boceprevir)." Schering-Plough Corporation
  11. O'Leary JG, McKenna GJ, Klintmalm GB, Davis GL (2013) "Effect of telaprevir on the pharmacokinetics of sirolimus in liver transplant recipients." Liver Transpl, 19, p. 463-5
  12. (2022) "Product Information. Fyarro (sirolimus protein-bound)." Aadi Bioscience, Inc.

Drug and food interactions

Moderate

amprenavir food

Applies to: amprenavir

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.

References (2)
  1. (2001) "Product Information. Agenerase (amprenavir)." Glaxo Wellcome
  2. Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM (2002) "Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice." Antimicrob Agents Chemother, 46, p. 1589-1590
Moderate

sirolimus protein-bound food

Applies to: sirolimus protein-bound

GENERALLY AVOID: Coadministration of protein-bound sirolimus intravenous suspension with grapefruit juice may increase the systemic exposure to sirolimus. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of sirolimus by certain compounds present in grapefruit. However, grapefruit juice primarily inhibits CYP450 3A4-mediated first-pass metabolism in the gut wall and may have limited effects on medications that are not administered orally. No formal studies evaluating the drug interaction potential of protein-bound sirolimus have been conducted. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

MANAGEMENT: The manufacturer recommends avoiding grapefruit and grapefruit juice during treatment with protein-bound sirolimus.

References (1)
  1. (2022) "Product Information. Fyarro (sirolimus protein-bound)." Aadi Bioscience, Inc.

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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