噻吩并吡啶类药物代谢的研究进展

抗血小板治疗因其强有效的降低动脉血栓的能力,成为了缺血性心脑血管疾病患者治疗的基础。噻吩并吡啶类药物是第一批被开发的血小板ADP受体拮抗剂,其母体药物均为无活性的前药,需经体内代谢转化为活性产物后才能对ADP受体P2Y12发挥抑制作用。对噻吩并吡啶类药物的代谢途径、代谢产物及其临床相互作用进行了综述。     

Response variability to clopidogrel: is tailored treatment,based on laboratory testing,the right solution?

Summary. Clopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y₁₂. Wide inter‐individual variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one‐third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost‐benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost‐effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise.     

The Degradation Chemistry of Prasugrel Hydrochloride: Part 1—Drug Substance

Prasugrel hydrochloride is the active ingredient in Effient™, a thienopyridine platelet inhibitor. An extensive study of the degradation chemistry of prasugrel hydrochloride (LY640315 hydrochloride) has been carried out on the drug substance (part I) and on the drug product (part II, future article) using a multidimensional approach including hydrolytic, oxidative, and photolytic stressing, computational chemistry, HPLC analysis, and structure elucidation by various spectroscopic techniques. The major degradation products formed from the drug substance under the various stress conditions have been isolated and structures unambiguously determined, and the pathways leading to these products have been proposed. Fourteen new (not previously disclosed) products were discovered and characterized, in addition to 4 degradation products that had been previously identified in the literature. The pathways indicate that prasugrel is susceptible to hydrolysis, autoxidation (both radical-initiated and single-electron mediated), and peroxide-mediated oxidation; in solution, prasugrel is susceptible to photodegradation.     

Prasugrel in Clopidogrel Nonresponders Undergoing Percutaneous Coronary Intervention: The RECLOSE-3 Study (REsponsiveness to CLOpidogrel and StEnt Thrombosis)

ObjectivesThis study sought to investigate the efficacy of prasugrel compared with clopidogrel in clopidogrel nonresponders.BackgroundClopidogrel nonresponsiveness is a strong marker of the risk of cardiac death and stent thrombosis after a percutaneous coronary intervention (PCI). It is unknown whether clopidogrel nonresponsiveness is a nonmodifiable risk factor or whether prasugrel with more potent and predictable platelet inhibition as measured by ex vivo techniques is associated with a positive effect on clinical outcome.MethodsThe RECLOSE-3 (REsponsiveness to CLOpidogrel and StEnt thrombosis) study screened clopidogrel nonresponders after a 600-mg loading dose of clopidogrel. Clopidogrel nonresponders switched to prasugrel (10 mg/day) the day of the PCI, and an adenosine diphosphate (ADP) test (10 μmol/l of ADP) was performed 6 days after the PCI. The primary endpoint was 2-year cardiac mortality. Patient outcome was compared with the RECLOSE-2–ACS study.ResultsWe screened 1,550 patients, of whom 302 were clopidogrel nonresponders. The result of the ADP test was 77.6 ± 6.2%. After switching to prasugrel, the ADP test result decreased to 47.1 ± 16.8%. The 2-year cardiac mortality rate was 4% in the RECLOSE-3 study and 9.7% in nonresponders of the RECLOSE-2–ACS study (p = 0.007). The definite and probable stent thrombosis rates were 0.7% and 4.4%, respectively (p = 0.004). On multivariable analysis, prasugrel treatment was related to the risk of 2-year cardiac death (hazard ratio: 0.32, p = 0.036).ConclusionsClopidogrel nonresponsiveness can be overcome by prasugrel (10 mg/day), and optimal platelet aggregation inhibition on prasugrel treatment is associated with a low rate of long-term cardiac mortality and stent thrombosis.     

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study

ObjectivesThe aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention.BackgroundPrasugrel is one of the preferred P2Y₁₂ platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients.MethodsBetween September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days.ResultsOf 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36).ConclusionsThis observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

Prevalence of CYP2C19 alleles,pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population

The extent to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity between studies. We used the polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) method for genotyping loss of function (LOF) allele, CYP2C19*2 and gain of function (GOF) allele, CYP2C19*17 in 163 patients undergoing PCI and 165 healthy volunteers from an ethnically distinctive Bangladeshi population. Thirty‐eight patients took prasugrel and 125 patients took clopidogrel among whom 30 patients had their clopidogrel active metabolites (CAM) determined by LC‐MS/MS 1–1.5 h after clopidogrel intake. All patients who underwent PCI had their P2Y12 per cent inhibition (PRI) measured by VerifyNow System. The impact of different genotypes on CAM and PRI were also determined. We did not find significant variation of CYP2C19*2 (P > 0.05) and CYP2C9*17 (P > 0.05) alleles among healthy volunteers and patients. CAM concentration as well as PRI by clopidogrel varied significantly (P < 0.05) based on genotypic variation of CYP2C19*2 and CYP2C19*17 individually. Such influence was not observed in case of prasugrel. Genotypic variation did not impact PRI but as a whole PRI by prasugrel was better than that of clopidogrel (P < 0.05). Due to presence of both of alleles the effect on PRI by clopidogrel could not be predicted, effectively indicating possible involvement of other factors. Genotype guided clopidogrel dose adjustment would be beneficial and therefore we propose mandatory genotyping before clopidogrel dosing. Prasugrel proved to be less affected by genotypic variability, but due to lack of sufficient long‐term toxicity data, caution would be adopted before substituting clopidogrel.