Drug Interactions between nirmatrelvir / ritonavir 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.

ADJUST DOSE: Coadministration of protein-bound sirolimus intravenous suspension with moderate or weak inhibitors of CYP450 3A4 may increase the systemic exposure to sirolimus, which is primarily metabolized by the isoenzyme and also a substrate of the P-glycoprotein (P-gp) 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 moderate dual inhibitors of CYP450 3A4 and P-gp such as diltiazem, erythromycin and verapamil, all of which are also substrates of CYP450 3A4 and P-gp. When 10 mg of sirolimus oral solution was administered with 120 mg of diltiazem in 18 healthy volunteers, sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.4- and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites, desacetyldiltiazem and desmethyldiltiazem. When sirolimus oral solution 2 mg once a day was coadministered with erythromycin ethylsuccinate 800 mg every 8 hours to steady state in 24 healthy volunteers, sirolimus Cmax and AUC increased by 4.4- and 4.2-fold, respectively, while erythromycin Cmax and AUC increased by 1.6- and 1.7-fold, respectively. Likewise, when sirolimus oral solution 2 mg once a day was coadministered with verapamil 180 mg every 12 hours to steady state in 25 healthy volunteers, sirolimus Cmax and AUC increased by 2.3- and 2.2-fold, respectively, while Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil both increased by 1.5-fold. Increased exposures to sirolimus may increase the risk of adverse effects such stomatitis, nausea, diarrhea, vomiting, myelosuppression, infections, hypokalemia, hyperglycemia, interstitial lung disease, edema, rash, alopecia, and hemorrhage.

MANAGEMENT: When administered concomitantly with moderate or weak CYP450 3A4 inhibitors, the manufacturer recommends reducing the dosage of protein-bound sirolimus intravenous suspension to 56 mg/m2. Clinical response and toxicities should be closely monitored, and the dosage of protein-bound sirolimus further adjusted as necessary. In addition, patients may also require monitoring for potentially increased effects of concomitant CYP450 3A4 inhibitors, as many are also substrates of CYP450 3A4 and/or P-gp and may be impacted by sirolimus. The prescribing information for concomitant medications should be consulted.