CYP3A4 inducers Sirolimus

Monitoring Monitor whole blood sirolimus concentrations in patients receiving concentration-controlled sirolimus. Monitoring is also necessary in patients likely to have altered drug metabolism, in patients at least 13 years of age who weigh less than 40 kg, in patients with hepatic impairment, and during coadministration of potent CYP3A4 inducers and inhibitors. 

Metabolism inducible. Susceptible to inhibition of metabolism by CYP3A4. (Tacrolimus and sirolimus appear to have similar interactions.)... 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

Drugs that Induce the cydochrome P450 isoenzyme CYP3A4 are predicted to lower sirolimus levels. Close monitoring is recommended. 

A clinical study in 14 healthy subjects found that rifampicin (rifampin) 600 mg daily for 6 days increased the clearance of a single 10-mg oral dose of sirolimus 5.5-fold, and reduced the AUC and maximum serum levels of sirolimus by 82% and 71%, respectively. Rifampicin is a potent inducer of the cytochrome P450 isoenzyme CYP3A4, the isoenzyme by which sirolimus is metabolised. Therefore concurrent use increases sirolimus metabolism and reduces its levels. The manufacturers say that concurrent use is not recommended. Rifabutin [a weak CYP3A4 inhibitor] and rifapentine [a moderate CYP3A4 inhibitor] are predicted to also... 

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