Department of Clinical Pharmacology, Zhong Shan Hospital, Fudan University, Shanghai, China.
Clin Ther. 2010 Mar;32(3):575-87. doi: 10.1016/j.clinthera.2010.03.015.
Cross-study comparisons suggest that systemic exposure (AUC) to rosuvastatin calcium, a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, may be approximately 2-fold higher in Asian subjects living in Asian countries than in white subjects living in Western countries.
This study was conducted to determine the pharmacokinetic characteristics of rosuvastatin and its metabolites after single and multiple doses of rosuvastatin in healthy Chinese subjects living in China.
This was an open-label, ascending single- and multiple-dose study. Subjects were randomly assigned to receive rosuvastatin 5, 10, or 20 mg. Each subject received 1 tablet of the assigned treatment on day 1 and days 4 through 10. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone were measured through 72 hours after administration of single doses and through 96 hours after administration of multiple doses. Blood samples were obtained within 30 minutes before dosing on days 7, 8, and 9 for the assessment of pharmacokinetic parameters at steady state. Noncompartmental pharmacokinetic analysis was performed to determine the C(max) and AUC(0-t) for rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone after single and multiple doses of rosuvastatin. Tolerability assessments were conducted throughout the study.
Of the 36 enrolled subjects, only 1 was female. The mean age of subjects in the rosuvastatin 5-, 10-, and 20-mg groups was 22.4, 21.3, and 22.4 years, respectively. Weight and height ranged from 54 to 85 kg and from 161 to 189 cm, respectively. Geometric mean C(max) values for rosuvastatin after administration of single doses of rosuvastatin 5, 10, and 20 mg were 8.33, 10.76, and 19.17 ng/mL, respectively; the corresponding geometric mean AUC(0-t) values were 57.63, 88.89, and 163.87 ng . h/mL. At steady state, values for C(max) were 8.31, 8.41, and 20.73 ng/mL; the corresponding geometric mean AUC values were 64.87, 77.29, and 178.64 ng . h/mL. After administration of multiple doses of rosuvastatin 5, 10, and 20 mg, the accumulation ratios were 1.23, 0.95, and 1.23, respectively, indicating minimal accumulation of rosuvastatin. Circulating concentrations of N-desmethyl rosuvastatin and rosuvastatin lactone were well below those of rosuvastatin after administration of single and multiple doses of rosuvastatin.
Increases in C(max), AUC(0-t), C(max,ss), and AUC(ss) were observed with increasing single and multiple doses of rosuvastatin 5, 10, and 20 mg. The increase in exposure with increasing doses was lower than would be expected under conditions of strict proportionality. Rosuvastatin exhibited little accumulation on repeated administration. All rosuvastatin doses were well tolerated in these Chinese subjects.
多项研究的交叉比较表明，与生活在西方国家的白种人相比，生活在亚洲国家的亚洲人使用瑞舒伐他汀钙（一种 3-羟基-3-甲基戊二酰基辅酶 A 还原酶抑制剂）时，其全身暴露（AUC）可能高出约 2 倍。
本研究旨在确定中国健康受试者单剂量和多剂量瑞舒伐他汀给药后的瑞舒伐他汀及其代谢物的药代动力学特征。
这是一项开放标签、递增的单剂量和多剂量研究。受试者被随机分配接受瑞舒伐他汀 5、10 或 20mg。每个受试者在第 1 天和第 4 天至第 10 天服用 1 片指定的治疗药物。单剂量给药后 72 小时和多剂量给药后 96 小时测量瑞舒伐他汀、N-去甲基瑞舒伐他汀和瑞舒伐他汀内酯的血浆浓度。在第 7、8 和 9 天给药前 30 分钟内采集血样，以评估稳态时的药代动力学参数。采用非房室药代动力学分析方法，确定瑞舒伐他汀 5、10 和 20mg 单剂量和多剂量给药后的 C(max)和 AUC(0-t)。在整个研究过程中进行耐受性评估。
在 36 名入组受试者中，只有 1 名为女性。瑞舒伐他汀 5、10 和 20mg 组受试者的平均年龄分别为 22.4、21.3 和 22.4 岁。体重和身高范围分别为 54 至 85kg 和 161 至 189cm。瑞舒伐他汀单剂量给药后，瑞舒伐他汀的几何均数 C(max)值分别为 8.33、10.76 和 19.17ng/mL；相应的几何均数 AUC(0-t)值分别为 57.63、88.89 和 163.87ng·h/mL。在稳态时，C(max)值分别为 8.31、8.41 和 20.73ng/mL；相应的几何均数 AUC 值分别为 64.87、77.29 和 178.64ng·h/mL。瑞舒伐他汀 5、10 和 20mg 多剂量给药后，蓄积比分别为 1.23、0.95 和 1.23，表明瑞舒伐他汀的蓄积很小。瑞舒伐他汀单剂量和多剂量给药后，N-去甲基瑞舒伐他汀和瑞舒伐他汀内酯的循环浓度均明显低于瑞舒伐他汀。
瑞舒伐他汀 5、10 和 20mg 单剂量和多剂量给药后，C(max)、AUC(0-t)、C(max,ss)和 AUC(ss)均增加。随着剂量的增加，暴露量的增加低于严格比例条件下的预期。瑞舒伐他汀在重复给药时几乎没有蓄积。这些中国受试者对所有瑞舒伐他汀剂量均耐受良好。
