University of Florida College of Medicine-Jacksonville, Jacksonville, FL 32209, USA.
Circ Cardiovasc Interv. 2011 Jun;4(3):273-9. doi: 10.1161/CIRCINTERVENTIONS.110.960997. Epub 2011 Apr 26.
Safety concerns have recently emerged based on a drug interaction between clopidogrel and proton pump inhibitors leading to reduced pharmacodynamic effects. However, whether such drug interaction is a class effect or a drug effect and if this can be modulated by timing of drug administration remains a matter of debate. The aim of this study was to assess the impact of high-dose pantoprazole therapy, a proton pump inhibitor with low potential to interfere with clopidogrel metabolism, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects.
This was a prospective, randomized, crossover study conducted in 20 healthy volunteers. Subjects were randomly assigned to receive pantoprazole (80 mg daily) administered concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy (600-mg loading dose followed by a 75-mg maintenance dose during all phases) in a crossover fashion with a 2- to 4-week washout period between treatments. All subjects had a 1-week treatment phase with a clopidogrel-only regimen with a 2- to 4-week washout period from randomization sequence. Platelet function was assessed by flow cytometric analysis of the status of phosphorylation of the vasodilator-stimulated phosphoprotein, light transmittance aggregometry after adenosine diphosphate stimuli, and VerifyNow P2Y(12) system at 3 time points: baseline, 24 hours after loading dose, and 1 week after maintenance dose. The primary end point was the comparison of P2Y(12) reactivity index assessed by vasodilator-stimulated phosphoprotein at 1 week. After 1 week, there were no significant difference in P2Y(12) reactivity index between the CONC and STAG regimens (least-squares mean±SEM, 56.0±3.9% versus 56.1±3.9%; P=0.974), as well as when compared with the clopidogrel-only regimen (61.0±3.9%; P=0.100 versus CONC and P=0.107 versus STAG). Further, no differences were observed at baseline and 24 hours between regimens. Concordant results were obtained by light transmittance aggregometry and VerifyNow P2Y(12) assays.
Pantoprazole therapy used at high doses is not associated with modulation of the pharmacodynamic effects of clopidogrel, irrespective of timing of drug administration.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01170533.
最近出现了与氯吡格雷和质子泵抑制剂之间的药物相互作用有关的安全性问题，导致药效降低。然而，这种药物相互作用是一种类效应还是药物效应，以及这种相互作用是否可以通过药物给药时间来调节，仍然存在争议。本研究的目的是评估高剂量泮托拉唑治疗（一种潜在干扰氯吡格雷代谢的质子泵抑制剂）同时或错开给药对氯吡格雷介导的药效学作用的影响。
这是一项在 20 名健康志愿者中进行的前瞻性、随机、交叉研究。受试者被随机分配接受泮托拉唑（每天 80 毫克）同时给药（CONC）或错开 8 至 12 小时（STAG），为期 1 周，同时接受氯吡格雷治疗（600 毫克负荷剂量，随后所有阶段均给予 75 毫克维持剂量），以交叉方式进行，两次治疗之间有 2 至 4 周的洗脱期。所有受试者均进行为期 1 周的氯吡格雷单药治疗，随机分组后有 2 至 4 周的洗脱期。通过流式细胞术分析血管扩张刺激磷酸蛋白的磷酸化状态、二磷酸腺苷刺激后的透光率聚集测定法和 VerifyNow P2Y(12)系统在 3 个时间点评估血小板功能：基线、负荷剂量后 24 小时和维持剂量后 1 周。主要终点是通过血管扩张刺激磷酸蛋白在 1 周时评估的 P2Y(12)反应性指数的比较。1 周后，CONC 和 STAG 方案之间的 P2Y(12)反应性指数没有显著差异（最小二乘均值±SEM，56.0±3.9%与 56.1±3.9%；P=0.974），与氯吡格雷单药治疗方案相比也没有差异（61.0±3.9%；P=0.100 与 CONC，P=0.107 与 STAG）。此外，方案之间在基线和 24 小时时没有观察到差异。透光率聚集测定法和 VerifyNow P2Y(12)测定法也得到了一致的结果。
高剂量泮托拉唑治疗不会调节氯吡格雷的药效学作用，无论给药时间如何。
