Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel

Background: Clopidogrel is a prodrug requiring metabolism by cytochrome P450 3A ( CYP(3)A) isoenzymes, including CYP3A5, in order to be active. It is controversial whether clopidogrel interacts with CYP3A inhibitors. We investigated the influence of CYP3A5 polymorphism on the drug interaction of clopidogrel. Methods: In phase 1 of the study, we administered clopidogrel to 16 healthy volunteers who had the CYP3A5 nonexpressor genotype (*3 allele) and 16 who had the CYP3A5 expressor genotype (*1 allele) with and without pretreatment with itraconazole, a potent CYP3A inhibitor. A platelet aggregation test was performed at baseline, 4 hours, 24 hours and 6 days after clopidogrel administration. In phase 2, we compared clinical outcomes of 348 patients treated with clopidogrel after successful coronary angioplasty with bare-metal stent implantation according to their CYP3A5 genotype; the primary end point was a composite of atherothrombotic events ( cardiovascular death, myocardial infarction and non-hemorrhagic stroke) within 1 and 6 months after stent implantation. Results: In phase 1, the change in platelet aggregation after clopidogrel administration and pretreatment with itraconazole was greater among the subjects with the CYP3A5 expressor genotype than among those with the non-expressor genotype: 24.9% ( standard deviation [ SD] 13.9%) v. 6.2% ( SD 13.5%) at 4 hours ( p < 0.001); 27.7% ( SD 16.5%) v. 2.5% ( SD 8.3%) at 24 hours ( p < 0.001); and 33.5% ( SD 18.6%) v. 17.8% ( SD 13.8%) at day 7 ( p < 0.01). In phase 2, atherothrombotic events occurred more frequently within 6 months after stent implantation among the patients with the non-expressor genotype than among those with the expressor genotype ( 14/193 v. 3/155; p = 0.023). Multivariable analysis showed that the CYP3A5 polymorphism was a predictor of atherothrombotic events in clopidogrel users. Interpretation: People with the CYP3A5 non-expressor genotype are vulnerable to drug interactions between clopidogrel and CYP3A inhibitors. This phenomenon may be associated with worse outcomes in patients with the non-expressor genotype who are given clopidogrel after coronary angioplasty and implantation of bare-metal stents.