AstraZeneca, Wilmington, DE, USA.
Clin Drug Investig. 2013 Apr;33(4):233-41. doi: 10.1007/s40261-013-0071-3.
Rosuvastatin has been shown to provide effective treatment of dyslipidaemia in patients with end-stage renal disease (ESRD) undergoing haemodialysis, but data from controlled trials are very limited on the pharmacokinetics and pharmacodynamics of rosuvastatin in this population.
The aim of the present study was to better define the pharmacokinetic and pharmacodynamic profiles of repeated doses of rosuvastatin at a starting dose of 10 mg/day in a group of patients with ESRD.
This was a single-centre, open-label study of rosuvastatin 10 mg daily, given over a 16-day treatment period in patients with ESRD undergoing chronic haemodialysis.
The study was carried out at a single site in the USA.
Patients aged 18-65 years with ESRD who had been on dialysis for ≥ 3 months were eligible for inclusion. Of 12 patients enrolled, 11 were included in the pharmacokinetic and pharmacodynamic analysis and all were included in the safety evaluation. The mean age of patients was 43.9 years (range 24-60 years). Five patients were Caucasian, six were black and one was Hispanic.
Patients received an oral dose of rosuvastatin 10 mg once daily in the morning for 16 consecutive days.
The primary objective was to estimate the degree of rosuvastatin accumulation in plasma by measuring the area under the plasma concentration time curve (AUC) from time zero to 24 h following a single dose of rosuvastatin 10 mg on day 1, and the AUC at steady state on day 15.
Following administration of single and multiple doses, plasma concentrations of rosuvastatin declined in an apparent bi-exponential manner and remained above the limit of assay detection throughout the entire sampling periods on both day 1 and day 15. Steady-state plasma concentrations of rosuvastatin were achieved by day 11. Little accumulation of rosuvastatin after repeated, once-daily dosing was observed; the geometric mean accumulation ratio for rosuvastatin was 1.37 (coefficient of variation = 36.4 %). Clearance of rosuvastatin and its metabolites via dialysis was minimal. Following rosuvastatin 10 mg daily for 16 days, total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B were reduced from baseline by 30.6 %, 38.9 % and 30.6 %, respectively. Rosuvastatin was well tolerated.
The degree of rosuvastatin accumulation observed in patients receiving dialysis is similar to that in healthy individuals. The results of the current study suggest that rosuvastatin 10 mg may be administered to patients with ESRD on chronic haemodialysis without need for dose reduction.
已有研究证实，瑞舒伐他汀（rosuvastatin）可有效治疗接受血液透析的终末期肾病（end-stage renal disease，ESRD）患者的血脂异常，但关于此类患者中瑞舒伐他汀药代动力学和药效动力学的对照试验数据非常有限。
本研究旨在更明确 ESRD 患者起始剂量为 10mg/天的瑞舒伐他汀重复剂量的药代动力学和药效动力学特征。
这是一项单中心、开放性研究，纳入了 12 例 ESRD 患者，给予瑞舒伐他汀 10mg/天，连续治疗 16 天。
研究在美国的一个单一地点进行。
纳入标准为年龄 18-65 岁、接受 ESRD 血液透析治疗≥3 个月的患者。12 例入组患者中，11 例纳入药代动力学和药效动力学分析，所有患者均纳入安全性评估。患者平均年龄为 43.9 岁（范围 24-60 岁）。5 例为白人，6 例为黑人，1 例为西班牙裔。
患者每天清晨口服瑞舒伐他汀 10mg，连续 16 天。
主要研究目的是通过测量第 1 天单次 10mg 剂量后 24 小时内的血浆浓度时间曲线下面积（area under the plasma concentration time curve，AUC），以及第 15 天的稳态 AUC，评估瑞舒伐他汀在血浆中的蓄积程度。
单次和多次给药后，瑞舒伐他汀的血浆浓度呈明显双指数下降，在第 1 天和第 15 天的整个采样期间，均持续高于检测下限。第 11 天达到稳态血浆浓度。多次每日 1 次给药后瑞舒伐他汀蓄积程度较小；瑞舒伐他汀的几何平均蓄积比为 1.37（变异系数=36.4%）。通过透析清除的瑞舒伐他汀及其代谢物很少。瑞舒伐他汀 10mg 每日 1 次治疗 16 天后，总胆固醇、低密度脂蛋白胆固醇和载脂蛋白 B 分别降低了 30.6%、38.9%和 30.6%。瑞舒伐他汀耐受性良好。
接受透析的患者中观察到的瑞舒伐他汀蓄积程度与健康个体相似。本研究结果表明，对于接受慢性血液透析的 ESRD 患者，无需减少剂量即可给予瑞舒伐他汀 10mg。
