Oral P2Y12 Inhibitors: Victims or Perpetrators? A Focused Review on Pharmacokinetic, Clinically Relevant Drug Interactions

Pharmacokinetic-based drug-drug interactions (DDI) largely contribute to therapeutic failures by decreasing a drug's safety or efficacy. In particular, clinically relevant DDIs generate major changes in plasma concentrations of the 'victim' drug exerted by the 'perpetrator' drug, which interferes with different pharmacokinetic steps. Polypharmacy significantly contributes to clinically relevant DDIs, but is unavoidable for complex patients, such as those with acute or chronic cardiovascular diseases with comorbidities. Oral P2Y12 inhibitors, namely clopidogrel, prasugrel and ticagrelor, are recommended for dual or single (clopidogrel) antiplatelet therapy following acute and chronic cardiovascular diseases, respectively, and urgent or elective percutaneous coronary interventions. Thus, an oral P2Y12 agent is often part of a necessary polypharmacy in patients with cardiovascular diseases. The authors critically review pharmacokinetic-related clinically relevant DDIs involving oral P2Y12 inhibitors, focusing on underlying mechanisms, which may reduce safety and effectiveness. Based on significant differences in pharmacokinetic and biotransformation, clopidogrel and ticagrelor are exposed to clinically relevant DDIs as victim or perpetrator drugs, while prasugrel is less susceptible to DDIs.