In Vitro Evaluation of Potential Drug-Drug Interactions with Ticagrelor: Cytochrome P450 Reaction Phenotyping, Inhibition, Induction, and Differential Kinetics

Ticagrelor is an orally administered, antiplatelet agent that inhibits the prothrombotic effects of ADP on the platelet by antagonizing the P2Y(12) receptor. Ticagrelor is a reversibly binding direct-acting P2Y(12) antagonist and does not require metabolic activation to achieve its antiplatelet effect. CYP3A4 and CYP3A5 appear to be the enzymes predominantly responsible for the formation of the ticagrelor active and inactive metabolites, AR-C124910XX and AR-C133913XX. The apparent K(m) values in human liver microsomes are 27.0 and 38.8 mu M, with V(max) values of 730 and 417 pmol/min/mg for AR-C124910XX and AR-C133913XX, respectively. Ticagrelor moderately inhibited CYP2C9 activity in human liver microsomes with an IC(50) of 10.5 mu M, while exhibiting little or no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1. In human liver microsomes, ticagrelor inhibited midazolam 4-hydroxylation with an IC(50) of 8.2 mu M, while activating 1'-hydroxylation of midazolam. Studies with recombinant enzymes suggested that cytochrome b(5) and CYP3A4 interactions play a significant role in this differential kinetic behavior. Evaluated in fresh human hepatocytes at concentration up to 20 mu M, ticagrelor was not an inducer of CYP1A2 or CYP3A4. Although ticagrelor exhibited a tendency for CYP2B6 and CYP2C9 induction, its potential to cause drug interactions via the induction of these enzymes is low when its exposure at a therapeutic dose is considered.