盐酸多奈哌齐在肾功能中度受损受试者中的稳态药代动力学及安全性
Steady-state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function.
作者信息
Nagy Christa F, Kumar Dinesh, Cullen Edward I, Bolton W Kline, Marbury Thomas C, Gutierrez Maria J, Hutman H Wayne, Pratt Raymond D
机构信息
Clinical Pharmacology, Eisai Medical Research Inc., Ridgefiled Park, NJ 07660, USA.
出版信息
Br J Clin Pharmacol. 2004 Nov;58 Suppl 1(Suppl 1):18-24. doi: 10.1111/j.1365-2125.2004.01803.x.
AIMS
To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single-dose and multiple-dose phases.
METHODS
This open-label study enrolled subjects with moderate renal impairment (creatinine clearance [CL(Cr)] 17-33 ml min(-1) 1.73 m(-2) body surface area) and age, weight and sex-matched healthy controls. A single-dose (5 mg donepezil) phase was followed by a 23-day multiple dose (5 mg day(-1) donepezil) steady-state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose.
RESULTS
Thirty-six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (C(max) 5.17 +/- 0.36 and 6.07 +/- 0.49 ng ml(-1); AUC(0-24) 76.05 +/- 5.54 and 77.45 +/- 4.49 ng.h ml(-1); mean maximum percentage inhibition [I(max)] red blood cell (RBC) AChE activity 32.07 +/- 2.00 and 31.69 +/- 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady-state conditions did not differ between renally impaired and healthy subjects (C(SS) 20.83 +/- 1.78 and 18.38 +/- 1.52 ng ml(-1); AUC(0-24) 500.0 +/- 42.8 and 441.1 +/- 36.4 ng.h ml(-1); degree of accumulation [R(A)] 6.98 +/- 0.59 and 5.94 +/- 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition [I(SS)] RBC AChE activity 65.11 +/- 2.52 and 60.62 +/- 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 +/- 1.96 and 20.23 +/- 0.64, respectively). Donepezil was well tolerated by both groups.
CONCLUSIONS
These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment.
目的
在单剂量和多剂量阶段，对中度肾功能损害受试者及匹配的健康对照者中多奈哌齐的药代动力学、药效动力学和安全性进行特征分析。
方法
本开放标签研究纳入了中度肾功能损害（肌酐清除率[CL(Cr)]为17 - 33 ml·min⁻¹·1.73 m⁻²体表面积）的受试者以及年龄、体重和性别匹配的健康对照者。先进行单剂量（5 mg多奈哌齐）阶段，随后是为期23天的多剂量（5 mg·day⁻¹多奈哌齐）稳态阶段。在首剂后长达144小时以及末次剂量后168小时测定多奈哌齐的药代动力学和药效动力学参数。
结果
共纳入36名受试者，其中19名肾功能损害者和17名健康对照者。单剂量多奈哌齐给药后，两组之间所有药代动力学和药效动力学参数相似（C(max)分别为5.17 ± 0.36和6.07 ± 0.49 ng·ml⁻¹；AUC(0 - 24)分别为76.05 ± 5.54和77.45 ± 4.49 ng·h·ml⁻¹；红细胞（RBC）乙酰胆碱酯酶（AChE）活性的平均最大抑制百分比[I(max)]分别为32.07 ± 2.00%和31.69 ± 2.45%，分别对应肾功能损害受试者和健康受试者）。稳态条件下的药代动力学参数在肾功能损害受试者和健康受试者之间无差异（C(SS)分别为20.83 ± 1.78和18.38 ± 1.52 ng·ml⁻¹；AUC(0 - 24)分别为500.0 ± 42.8和441.1 ± 36.4 ng·h·ml⁻¹；蓄积度[R(A)]分别为6.98 ± 0.59和5.94 ± 0.53，分别对应肾功能损害受试者和健康受试者）。稳态时主要药效动力学参数在肾功能损害受试者和健康受试者中也相似（RBC AChE活性的平均抑制百分比[I(SS)]分别为65.11 ± 2.52和60.62 ± 2.95）。两组之间的蛋白结合也相似（游离多奈哌齐百分比分别为23.54 ± 1.96和20.23 ± 0.64）。两组对多奈哌齐耐受性均良好。
结论
这些结果表明，多奈哌齐给药至稳态后药代动力学未改变，且多奈哌齐可安全用于中度肾功能损害受试者。
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