Sica D A, Marino M R, Hammett J L, Ferreira I, Gehr T W, Ford N F
Division of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Clin Pharmacol Ther. 1997 Dec;62(6):610-8. doi: 10.1016/S0009-9236(97)90080-1.
An open-label, multiple-dose, parallel-group study was conducted to evaluate the pharmacokinetics of the angiotensin II receptor antagonist irbesartan in subjects with varying degrees of renal function.
Forty subjects were divided into four treatment groups on the basis of 24-hour creatinine clearance (CLCR): normal renal function (> 75 ml/min/1.73 m2), mild to moderate renal impairment (30 to 74 ml/min/1.73 m2), severe renal impairment (< 30 ml/min/1.73 m2), and maintenance hemodialysis. Subjects received 100 mg irbesartan daily for 8 days (or 300 mg daily for 9 days for the hemodialysis group). Serial blood and urine samples were collected for 24 hours after the first and last of eight successive daily doses. In addition, arterial and venous blood samples were collected during two hemodialysis sessions from subjects requiring maintenance hemodialysis.
There was no statistically significant linear relationship between CLCR and maximum plasma concentrations, dose-adjusted area under the plasma concentration time curve values on days 1 or 8, or any other pharmacokinetic parameters among the renal function groups studied. There was no indication of drug accumulation with repetitive dosing. In the subjects receiving hemodialysis, arterial-venous concentration differences for irbesartan were negligible, suggesting that this compound is not cleared through hemodialysis. In addition, irbesartan was well tolerated.
Based on pharmacokinetic parameters, no starting dose adjustment is necessary in subjects with mild to severe renal impairment, inclusive of hemodialysis. Subjects with volume depletion may have an exaggerated response to an initial dose of irbesartan and, under such circumstances, volume depletion should be corrected or a lower starting dose of irbesartan should be considered.
开展一项开放标签、多剂量、平行组研究，以评估血管紧张素II受体拮抗剂厄贝沙坦在不同程度肾功能受试者中的药代动力学。
根据24小时肌酐清除率（CLCR）将40名受试者分为四个治疗组：肾功能正常（>75 ml/min/1.73 m²）、轻度至中度肾功能损害（30至74 ml/min/1.73 m²）、重度肾功能损害（<30 ml/min/1.73 m²）和维持性血液透析组。受试者每日服用100 mg厄贝沙坦，共8天（血液透析组每日服用300 mg，共9天）。在连续8天每日首次和末次给药后24小时收集系列血液和尿液样本。此外，在两次血液透析过程中，从需要维持性血液透析的受试者中采集动脉和静脉血样本。
在所研究的肾功能组中，CLCR与最大血浆浓度、第1天或第8天的剂量校正血浆浓度-时间曲线下面积值或任何其他药代动力学参数之间，均无统计学显著的线性关系。重复给药未显示药物蓄积迹象。在接受血液透析的受试者中，厄贝沙坦的动静脉浓度差异可忽略不计，表明该化合物不能通过血液透析清除。此外，厄贝沙坦耐受性良好。
基于药代动力学参数，轻度至重度肾功能损害受试者（包括血液透析患者）无需调整起始剂量。血容量不足的受试者可能对初始剂量的厄贝沙坦反应过度，在这种情况下，应纠正血容量不足或考虑使用较低的厄贝沙坦起始剂量。
