Rhabdomyolysis during concomitant ticagrelor and rosuvastatin - a breast cancer resistance protein -mediated drug interaction?

We present three patients diagnosed with rhabdomyolysis 1-6 months after the initiation of concomitant rosuvastatin and ticagrelor medication. A literature review and FDA adverse event reporting system revealed more than forty reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including three with a fatal outcome. We show that ticagrelor inhibits BCRP-, OATP1B1-, OATP1B3- and OATP2B1-mediated transport of rosuvastatin in vitro with half-maximal unbound inhibitory concentrations of 0.36 μM, 4.13 μM, 7.5 μM and 3.26 μM, respectively. A static drug interaction model predicted that ticagrelor may inhibit intestinal BCRP and thus increase rosuvastatin plasma exposure 2.1-fold, whereas the OATP-mediated hepatic uptake of rosuvastatin should not be inhibited due to relatively low portal ticagrelor concentrations. Taken together, concomitant use of ticagrelor with rosuvastatin may increase the systemic exposure to rosuvastatin and the risk of rosuvastatin-induced rhabdomyolysis. Further studies are warranted to investigate the potential pharmacokinetic interaction between ticagrelor and rosuvastatin in humans.