Drug Interactions between Aricept and dabrafenib

MONITOR: Coadministration with dabrafenib may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4 and/or 2C9. Dabrafenib has been found in vitro to be an inducer of these isoenzymes. Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib; however, transient inhibition of CYP450 isoenzymes may be observed during the first few days of treatment. In 12 study subjects, administration of the CYP450 3A4 probe substrate midazolam following repeat doses of dabrafenib 150 mg twice daily for 15 days reduced midazolam peak plasma concentration (Cmax) by 61% and systemic exposure (AUC) by 74%. When a single 15 mg dose of warfarin was coadministered similarly with dabrafenib, the AUC of S(-) warfarin decreased by 37% and that of R(+) decreased by 33%. S(-) warfarin, the biologically more active enantiomer, is primarily metabolized by CYP450 2C9, while R(+) warfarin is a substrate of CYP450 3A4 and 1A2.

MANAGEMENT: Caution is advised when dabrafenib is prescribed with drugs that undergo metabolism by CYP450 3A4 and/or 2C9. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever dabrafenib is added to or withdrawn from therapy. Significantly reduced plasma concentrations and loss of efficacy may occur with sensitive substrates of CYP450 3A4 or 2C9 such as hormonal contraceptives, immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus), ivacaftor, and warfarin-type anticoagulants. Alternatives to these medications should be considered if possible.