Rhabdomyolysis during concomitant ticagrelor and rosuvastatin: A breast cancer resistance protein‐mediated drug interaction?

Abstract

We present 3 patients diagnosed with rhabdomyolysis 1–6 months after the initiation of concomitant rosuvastatin and ticagrelor medication. A literature review and Food and Drug Administration adverse event reporting system revealed >40 reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including 3 with a fatal outcome. We show that ticagrelor inhibits breast cancer resistance protein‐, organic anion transporting polypeptide (OATP) 1B1‐, 1B3‐ and 2B1‐mediated transport of rosuvastatin in vitro with half‐maximal unbound inhibitory concentrations of 0.36, 4.13, 7.5 and 3.26 μM, respectively. A static drug interaction model predicted that ticagrelor may inhibit intestinal breast cancer resistance protein 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.

Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin

“…The effect size of ticagrelor on rosuvastatin pharmacokinetics in this study was in the vicinity of these previous findings. According to our static interaction model, inhibition of intestinal BCRP by ticagrelor would increase the plasma exposure to rosuvastatin on average twofold 13 . This is well within 2‐fold of the observed value 2.6, which is a commonly applied criterion for accuracy of drug–drug interaction predictions.…”

“…According to our model, inhibition of OATP1B1, OATP1B3, and OATP2B1 by ticagrelor should have no effect on rosuvastatin concentrations. In our previously published static interaction model, 13 we did not include renal BCRP, as it has been unclear whether renal BCRP has any role in the pharmacokinetics of rosuvastatin. In this clinical study, however, we saw a decrease in the Cl renal of rosuvastatin in the ticagrelor phase.…”

“…Genomic DNA was extracted from buffy coats using the Maxwell 16 LEV Blood DNA Kit on a Maxwell 16 Research automated nucleic acid extraction system (Promega, Madison, WI). The participants were genotyped for the ABCG2 c.421C>A (rs2231142, p.Q141K) and SLCO1B1 c.388A>G (rs2306283, p.N130D), c.521T>C (rs4149056, p.V174A), and c.1929A>C (rs34671512, p.L463F) single nucleotide variants with a clinical pharmacogenetic panel test available at the Genetics laboratory of the HUS Diagnostic Center (Helsinki University Hospital, Helsinki, Finland), as described previously 13 . SLCO1B1 *‐alleles were named according to the Pharmacogene Variation Consortium core allele definitions 26 …”

“…Static interaction predictions between ticagrelor and rosuvastatin were carried out using the equations and rosuvastatin parameters reported previously ( Tables ) 13,27–36 . For prediction of the effect of ticagrelor on renal BCRP, unbound C max of ticagrelor was used.…”

“…Although usually well‐tolerated, rosuvastatin can cause muscle symptoms of varying severity, especially at higher doses 1 . Previously published case reports have suggested that concomitant use of rosuvastatin and the platelet‐inhibitor ticagrelor may have led to severe, even fatal, cases of rosuvastatin‐induced rhabdomyolysis 2–13 . Because the risk of rosuvastatin‐induced myotoxicity is concentration‐dependent, the rhabdomyolysis cases suggest a potential pharmacokinetic drug–drug interaction between ticagrelor and rosuvastatin.…”