de Zeeuw D, Remuzzi G, Kirch W
University of Groningen, The Netherlands.
J Hum Hypertens. 1997 Sep;11 Suppl 2:S37-42.
Five clinical studies were conducted to investigate the pharmacokinetic profile and safety of candesartan cilexetil in patients with either normal or impaired renal or hepatic function. Participants in these open-label, single- or parallel-group prospective studies were administered candesartan cilexetil 8 or 12 mg as a single oral dose and then, in all but one study, as a repeated once-daily oral dose regimen. A total of 94 patients of either gender aged between 18 and 75 years with normal or mild to moderate hepatic dysfunction (Study 1) and normal or mild to moderate/severe renal dysfunction (Studies 2-5) were included. Subjects recruited to all studies evaluating the effect of renal impairment also had some degree of hypertension. Patients with mild to moderate hepatic impairment showed no significant differences in the key plasma pharmacokinetic parameters or plasma protein binding profile of candesartan compared with healthy volunteers. In patients with mild to moderate or severe renal impairment there were significant increases in the maximum plasma concentration, area under the plasma drug concentration-time curve and elimination half-life of candesartan and its inactive metabolite (CV-15959) when compared to volunteers with normal renal function following repeated administration of candesartan cilexetil 8 or 12 mg. However, there was no evidence of accumulation following treatment with the 8 mg dose apart from those with severe disease requiring dialysis. Nevertheless, dialysis itself did not appear to affect the pharmacokinetic profile of candesartan or that of CV-15959. Candesartan cilexetil was found to have a good safety profile and to be well tolerated by patients with hepatic or renal impairment. There were no clinically relevant changes detected in vital signs, laboratory safety parameters or in ECG readings. The most common adverse events were headache and dizziness. This series of studies show that candesartan cilexetil 8 mg once daily is suitable for administration to patients with mild to moderate renal or hepatic impairment with no need for additional dose adjustment. A lower starting dose may be appropriate in patients with severe renal impairment including those requiring dialysis.
开展了五项临床研究，以调查坎地沙坦酯在肾功能或肝功能正常或受损患者中的药代动力学特征及安全性。这些开放标签、单组或平行组前瞻性研究的参与者接受了8毫克或12毫克坎地沙坦酯的单次口服剂量，除一项研究外，其余研究均采用每日一次的重复口服给药方案。共有94名年龄在18至75岁之间、肝功能正常或轻度至中度受损（研究1）以及肾功能正常或轻度至中度/重度受损（研究2至5）的男女患者纳入研究。所有评估肾功能损害影响的研究招募的受试者也患有一定程度的高血压。与健康志愿者相比，轻度至中度肝功能损害患者的坎地沙坦关键血浆药代动力学参数或血浆蛋白结合情况无显著差异。与肾功能正常的志愿者相比，在重复给予8毫克或12毫克坎地沙坦酯后，轻度至中度或重度肾功能损害患者的坎地沙坦及其无活性代谢物（CV - 15959）的最大血浆浓度、血浆药物浓度 - 时间曲线下面积和消除半衰期显著增加。然而，除了患有需要透析的严重疾病的患者外，8毫克剂量治疗后没有蓄积的证据。尽管如此，透析本身似乎并未影响坎地沙坦或CV - 15959的药代动力学特征。发现坎地沙坦酯具有良好的安全性，肝肾功能受损患者对其耐受性良好。生命体征、实验室安全参数或心电图读数均未检测到临床相关变化。最常见的不良事件是头痛和头晕。这一系列研究表明，每日一次8毫克坎地沙坦酯适用于轻度至中度肾或肝功能损害患者，无需额外调整剂量。对于包括需要透析的患者在内的严重肾功能损害患者，较低的起始剂量可能更为合适。
