Thebault J J, Kieffer G, Lowe G D, Nimmo W S, Cariou R
Institut Aster, Hôpital Cognacq Paris, France.
Semin Thromb Hemost. 1999;25 Suppl 2:9-14.
The effect of repeated doses of clopidogrel, a novel platelet ADP-receptor antagonist, on platelet aggregation and its tolerance were assessed in two randomized, double-blind studies in healthy male adults. In each of the four successive dose groups in Study I, 6 subjects received either clopidogrel 25, 50, 100, or 150 mg once daily and 2 received placebo for 16 days, according to a rising dose design. In each of the three successive treatment groups of Study II, 9 subjects received clopidogrel (50, 75, or 100 mg once daily) in the morning, 3 received triclopidine 250 mg twice daily and 3 received placebo for 14 days. In both studies, the inhibition of platelet aggregation induced by 5 microM of ADP was measured before dosing (baseline), then at regular intervals during and after treatment. Bleeding time was generally assessed at the same time points as platelet aggregation. In both studies, the inhibition of platelet aggregation reached steady state after day 6 dosing. Mean steady-state percent inhibition of platelet aggregation was 30%, 46%, 53%, and 73% for clopidogrel 25, 50, 100, and 150 mg, respectively, in Study I; and 54%, 52%, 47%, and 43% for clopidogrel 50, 75, 100 mg, and for ticlopidine, respectively, in Study II. After treatment discontinuation, statistically significant inhibition of platelet aggregation persisted for up to 8 days. In Study I, up to 75 mg repeated doses, mean bleeding time prolongation factor did not exceed 2, but increased further to 3.5 and 5.5 at a clopidogrel dose of 100 mg and 150 mg, respectively. In study II, prolongation factors during treatment did not exceed 2.2 for clopidogrel (in the 75 mg dose group) and 1.6 for ticlopidine 500 mg. Recovery of bleeding time was observed within 7-8 days. Treatments were well tolerated, and no serious clinical events or important changes in laboratory parameters were recorded. These data were consistent with those obtained in atherosclerotic patients and showed that the plateau response for the inhibition of platelet aggregation was reached at the 75 mg dose, for which bleeding time prolongation was approximately 2.
在两项针对健康成年男性的随机、双盲研究中，评估了新型血小板 ADP 受体拮抗剂氯吡格雷重复给药对血小板聚集的影响及其耐受性。在研究 I 的四个连续剂量组中，根据剂量递增设计，每组 6 名受试者每日一次分别接受 25、50、100 或 150 mg 氯吡格雷治疗，2 名受试者接受安慰剂治疗，为期 16 天。在研究 II 的三个连续治疗组中，每组 9 名受试者于上午接受氯吡格雷（每日一次，剂量分别为 50、75 或 100 mg）治疗，3 名受试者每日两次接受 250 mg 噻氯匹定治疗，3 名受试者接受安慰剂治疗，为期 14 天。在两项研究中，于给药前（基线）、治疗期间及治疗后定期测量 5 μM ADP 诱导的血小板聚集抑制情况。出血时间一般在与血小板聚集相同的时间点进行评估。在两项研究中，给药第 6 天后血小板聚集抑制达到稳态。在研究 I 中，氯吡格雷 25、50、100 和 150 mg 组血小板聚集的平均稳态抑制率分别为 30%、46%、53% 和 73%；在研究 II 中，氯吡格雷 50、75、100 mg 组及噻氯匹定组血小板聚集的平均稳态抑制率分别为 54%、52%、47% 和 43%。停药后，血小板聚集抑制作用在长达 8 天内仍具有统计学意义。在研究 I 中，重复剂量达 75 mg 时，平均出血时间延长因子不超过 2，但氯吡格雷剂量为 100 mg 和 150 mg 时，该因子分别进一步增至 3.5 和 5.5。在研究 II 中，氯吡格雷（75 mg 剂量组）治疗期间出血时间延长因子不超过 2.2，噻氯匹定 500 mg 组不超过 1.6。7 - 8 天内观察到出血时间恢复。治疗耐受性良好，未记录到严重临床事件或实验室参数的重要变化。这些数据与在动脉粥样硬化患者中获得的数据一致，表明在 75 mg 剂量时达到血小板聚集抑制的平台反应，此时出血时间延长约为 2 倍。
