Effects of N ilotinib on Drug Metabolizing Enzymes and Drug Transport Systems
Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In addition, single-dose administration of Tasigna with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%. Caution should be exercised when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index. Since warfarin is metabolized by CYP2C9 and CYP3A4 it should be avoided if possible.
In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and thereby has the potential to decrease the concentrations of drugs which are eliminated by these enzymes.
Nilotinib inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised.
Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes
Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly.
Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold. [ See Box Warning and Warnings and Precautions (5. 7 ) ] .
Rifampicin: In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.
Drugs that Inhibit Drug Transport Systems
Nilotinib is a substrate of the efflux transporter P-glycoprotein (Pgp, ABCB1). If Tasigna is administered with drugs that inhibit Pgp, increased concentrations of nilotinib are likely, and caution should be exercised.