Zhou Xiao-Jian, Swan Suzanne, Smith William B, Marbury Thomas C, Dubuc-Patrick Gloria, Chao George C, Brown Nathaniel A
Idenix Pharmaceuticals, Inc., One Kendall Square, Building 1400, Cambridge, MA 02139, USA.
Antimicrob Agents Chemother. 2007 Dec;51(12):4231-5. doi: 10.1128/AAC.00557-07. Epub 2007 Sep 17.
This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL(CR)), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL(R)), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL(R) and CL(CR). In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of approximately 45%, representing a approximately 23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.
本研究评估了肾功能损害对替比夫定药代动力学的影响。根据肌酐清除率（CL(CR)），将36名受试者分为5个肾功能组中的1组，每组6至8名受试者：肾功能正常；轻度、中度或重度肾功能损害；或需要血液透析的终末期肾病[ESRD]。受试者分别接受600 mg（正常功能和轻度损害）、400 mg（中度损害）或200 mg（重度损害和ESRD）的单次口服替比夫定剂量；在48小时内收集血浆和/或尿液样本进行药代动力学分析。所有受试者对替比夫定耐受性良好。600 mg替比夫定在轻度肾功能损害受试者和肾功能正常受试者中的药代动力学具有可比性。同样，对于中度至重度损害（包括ESRD）的受试者，200至400 mg的减量产生的血浆暴露与肾功能正常的受试者相似。这些结果表明，替比夫定的药代动力学取决于肾功能，尤其是对于中度至重度肾功能损害或ESRD的受试者。随着肾功能恶化，替比夫定的表观总血浆清除率、肾清除率（CL(R)）和尿排泄量均降低。CL(R)与CL(CR)之间建立了线性关系。在ESRD受试者中，常规的3.5至4小时血液透析疗程以约45%的提取率从血浆中清除替比夫定，这意味着总暴露量降低了约23%。这些结果表明，虽然轻度肾功能损害的受试者似乎无需调整替比夫定剂量，但对于中度至重度肾功能损害或ESRD的受试者，为了实现最佳血浆暴露，有必要调整剂量。
