Ticagrelor and Statins: Dangerous Liaisons?

Abstract

Polypharmacy is often necessary in complex, chronic, comorbid and cardiovascular patients and is a known risk factor for potential drug-drug interaction (DDI) that can cause adverse reactions (toxicity or therapeutic failure). Anti-thrombotic drugs (largely low-dose aspirin and a platelet P2Y12 receptor inhibitor) and statins are among the most co-administered drugs in cardiovascular patients. Ticagrelor is a selective antagonist of the platelet P2Y12-receptor, highly effective in inhibiting platelet aggregation and bio-transformed by the CYP3A4 and substrate of transporters, such as the breast cancer resistance protein (BCRP). Statins have different pharmacokinetic profiles; some undergo CYP3A4-mediated metabolism; rosuvastatin is primarily metabolized by the CYP2C9; and they have different affinities for drug transporters. Rhabdomyolysis is a very rare but severe adverse event, which is specific for statins which can be triggered by DDIs that increase statin's concentrations through blockade of their biotransformation and/or elimination. Large pharmacovigilance and small observational studies reported increased rhabdomyolysis in patients treated with some statins and ticagrelor but not aspirin, clopidogrel or prasugrel. Recent studies in vitro, pharmacokinetic trials and in silico drug modelling identified and validated the BCRP inhibition by ticagrelor, as a mechanism contributing to the DDI with statins, as 'victim' drugs, leading to increased rhabdomyolysis. While the clinical impact of this DDI deserves further investigation, a careful evaluation should be advised when ticagrelor is co-prescribed with some statins.

Keywords: Cytochrome P450; Drug interactions; Rhabdomyolysis; Statins; Ticagrelor; Transporters.

Fig. 1

Possible mechanisms underlying the clinically relevant interactions between ticagrelor as perpetrator drug and some statins as victim drugs. Upper panels: pathways of statin metabolism from the small intestine to the liver via the portal blood and to the downstream tissues and organs via the systemic circulation; ticagrelor inhibits the membrane transporters BCRP and P-gp (statin efflux/metabolism) in the enterocytes on  the gut lumen and the biotransforming CYP3A4 enzyme, thus blocking some steps of the elimination and biotransformation of statins. Lower panels: as a consequence of a reduced elimination, the co-administration of ticagrelor with some statins leads to increased plasma levels up to 2-folds of the statins and to potential severe DDIs; comorbidities (e.g. renal failure and ageing), chronic/occasional polypharmacy (e.g. gemfibrozil, anti-hypertensive or anti-microbic agents) and the statin daily dose can concur to cause severe adverse reactions. Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome; Met, metabolite(s); P-gp, P-glycoprotein; and OATP, organic anion–transporting polypeptides