Drug Interactions between sirolimus and Technivie

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may significantly increase the plasma concentrations of sirolimus following oral administration. Sirolimus is a substrate of both CYP450 3A4 isoenzyme and P-gp efflux transporter, thus their inhibition in the intestine can enhance the absorption of sirolimus. In 23 healthy volunteers, administration of a single 5 mg dose of sirolimus with the potent dual CYP450 3A4/P-gp inhibitor ketoconazole (200 mg/day orally for 10 days) increased mean sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 4- and 11-fold, respectively. Likewise, 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 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. Another dual 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. When sirolimus 2 mg once a day was coadministered with the moderate dual inhibitor erythromycin (ethylsuccinate salt 800 mg every 8 hours) in 24 study subjects, sirolimus Cmax and AUC increased by more than 4-fold each, while erythromycin Cmax and AUC also increased by more than 1.5-fold each.

MANAGEMENT: Concomitant use of sirolimus with potent CYP450 3A4 and/or P-gp inhibitors should generally be avoided. The manufacturers of posaconazole and voriconazole consider coadministration with sirolimus to be contraindicated. Some authorities recommend avoiding concomitant use of sirolimus during and for 2 weeks after treatment with itraconazole.

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CONTRAINDICATED: Coadministration of ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, may significantly increase the blood concentrations of tacrolimus, sirolimus, and everolimus. The proposed mechanism involves ritonavir inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of these immunosuppressants. Enhanced oral bioavailability due to inhibition of intestinal P-glycoprotein (P-gp) efflux transporter by ritonavir, paritaprevir, and dasabuvir may also contribute. When a single dose of tacrolimus was administered with ombitasvir/paritaprevir/ritonavir in healthy study subjects, tacrolimus peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) increased by approximately 4.3-, 85.8- and 24.6-fold, respectively, compared to tacrolimus administered alone. Likewise, sirolimus Cmax, AUC and Cmin increased by approximately 6.4-, 38.0- and 19.6-fold, respectively, while everolimus Cmax, AUC and Cmin increased by approximately 4.7-, 27.1- and 16.1-fold, respectively, when coadministered with ombitasvir/paritaprevir/ritonavir plus dasabuvir. Single-dose tacrolimus Cmax, AUC and Cmin increased by approximately 4.0-, 57.1-fold and 16.6-fold when coadministered with ombitasvir/paritaprevir/ritonavir plus dasabuvir

MANAGEMENT: Concomitant use of tacrolimus, sirolimus, or everolimus in combination with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, is considered contraindicated.

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