Lefèvre G, Duval M, Gauron S, Brookman L J, Rolan P E, Morris T M, Piraino A J, Morgan J M, Palmisano M, Close P
Laboratoires Ciba-Geigy, Ruell-Malmaison, France.
Clin Pharmacol Ther. 1997 Jul;62(1):50-9. doi: 10.1016/S0009-9236(97)90151-X.
To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function.
Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg.
Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four.
A dose reduction by a factor of six is recommended for persons with severe renal failure.
与肾功能正常的受试者相比，研究去纤苷在不同程度肾功能损害受试者中的药代动力学和药效学。
8名肾功能正常（肌酐清除率>90 ml/分钟）的受试者在30分钟内静脉注射0.5 mg/kg去纤苷。4名轻度肾衰竭（肌酐清除率在61至90 ml/分钟之间）的受试者接受0.5 mg/kg。5名中度肾衰竭（肌酐清除率在31至60 ml/分钟之间）的受试者接受0.25 mg/kg。6名重度肾衰竭（肌酐清除率<31 ml/分钟）的受试者接受0.125 mg/kg。
特定最大浓度值（校正至1 mg/kg剂量的最大浓度）随肌酐清除率降低而略有增加。与健康受试者相比，轻度、中度和重度肾衰竭受试者的血浆浓度-时间曲线下平均特定面积分别增加了1.15、2.83和7.0倍。在所有四组中，去纤苷的总尿排泄量约为剂量的55%至60%；中度和重度肾衰竭受试者的消除延迟。去纤苷的总清除率和肾清除率与肌酐清除率成正比。去纤苷的总血浆清除率与药物的肾清除率成正比。尽管剂量降低，但中度和重度肾衰竭受试者的活化部分凝血活酶时间延长。中度肾衰竭受试者的动态活化部分凝血活酶时间曲线下面积尽管剂量降低了两倍，但仍与健康受试者相同。尽管剂量降低了四倍，但重度肾衰竭受试者的动态曲线下面积增加了约1.5倍。
建议重度肾衰竭患者将剂量降低六倍。
