Blockbuster interactions: are they bad for the patient?

This editorial refers to ‘Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study’, by Y. Park et al. , doi:10.1093/eurheartj/ehs083 Variability in individual responsiveness to clopidogrel has been widely acknowledged and investigated in these last few years. Clopidogrel inhibits platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate (ADP) receptor. It has become established that a significant proportion of patients display high platelet reactivity on clopidogrel treatment and thus are exposed to a greater risk of death, myocardial infarction, and stent thrombosis.1One source of the variability is the hepatic metabolism of clopidogrel, which is a prodrug that requires metabolic activation to generate its active thiol metabolite.2 Specifically, clopidogrel activation requires two oxidative steps involving a variety of hepatic enzymes from the cytochrome P450 (CYP) system, the major catalyst of oxidative biotransformation reactions involved in drug metabolism.3 CYP2C19 is involved in both steps and contributes to an estimated 45% of the 2-oxo-clopidogrel and 21% of active metabolite generation.4 CYP3A4/5, another CYP isoenzyme, is also a significant contributor to clopidogrel bioactivation. Loss-of-function CYP2C19 genetic variants have been associated with reduced concentrations of active drug metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events.5 On the other hand, there is no common genetic polymorphism associated with alteration in CYP3A4 activity.Among the non-genetic sources of variability, drug–drug interaction (DDI) is one of major concern; DDI may inhibit or induce the function of CYP isoenzymes and consequently affect the response to CYP-metabolized drugs including clopidogrel.3 Hence, CYP3A4 inhibitors and inducers are considered as important candidates to interfere with clopidogrel response (Figure 1). The antifungal agents ketoconazole and itraconazole are potent inhibitors of CYP3A4. In a study conducted in healthy subjects, ketoconazole co-administration resulted …