肾功能损害对 GLP-1 类似物利拉鲁肽药代动力学的影响。
Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide.
机构信息
Novo Nordisk A/S, Bagsvaerd, Denmark.
出版信息
Br J Clin Pharmacol. 2009 Dec;68(6):898-905. doi: 10.1111/j.1365-2125.2009.03536.x.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- Patients with Type 2 diabetes are likely to have or to develop renal impairment, which affects the pharmacokinetics of some antidiabetic treatments. * Whether dosing of the once-daily human glucagon-like peptide-1 analogue liraglutide should be modified in patients with renal impairment has not previously been studied.
WHAT THIS STUDY ADDS
- Renal dysfunction was not found to increase the exposure of liraglutide. * Hence, no dose adjustment is expected to be required in patients with Type 2 diabetes and renal impairment treated with liraglutide.
AIMS
To investigate whether dose adjustment of the once-daily human glucagon-like peptide-1 analogue liraglutide is required in patients with varying stages of renal impairment.
METHODS
A cohort of 30 subjects, of whom 24 had varying degrees of renal impairment and six had normal renal function, were given a single dose of liraglutide, 0.75 mg subcutaneously, and completed serial blood sampling for plasma liraglutide measurements for pharmacokinetic estimation.
RESULTS
No clear trend for change in pharmacokinetics was evident across groups with increasing renal dysfunction. While the between-group comparisons of the area under the liraglutide concentration-curve (AUC) did not demonstrate equivalence [estimated ratio AUC(severe)/AUC(healthy) 0.73, 90% confidence interval (CI) 0.57, 0.94; and AUC (continuous ambulatory peritoneal dialysis)(CAPD)/AUC(healthy) 0.74, 90% CI 0.56, 0.97], the regression analysis of log(AUC) for subjects with normal renal function and mild-to-severe renal impairment showed no significant effect of decreasing creatinine clearance on the pharmacokinetics of liraglutide. The expected AUC ratio between the two subjects with the lowest and highest creatinine clearance in the study was estimated to be 0.88 (95% CI 0.58, 1.34) (NS). Degree of renal impairment did not appear to be associated with an increased risk of adverse events.
CONCLUSIONS
This study indicated no safety concerns regarding use of liraglutide in patients with renal impairment. Renal dysfunction was not found to increase exposure of liraglutide, and patients with Type 2 diabetes and renal impairment should use standard treatment regimens of liraglutide. There is, however, currently limited experience with liraglutide in patients beyond mild-stage renal disease.
已知信息：患有 2 型糖尿病的患者可能会出现或发展为肾功能损害，这会影响某些抗糖尿病治疗的药代动力学。此前尚未研究过肾功能损害患者单次给予人胰高血糖素样肽-1 类似物利拉鲁肽的剂量是否需要调整。
研究新增：未发现肾功能障碍会增加利拉鲁肽的暴露。因此，预计肾功能损害的 2 型糖尿病患者使用利拉鲁肽时无需调整剂量。
目的：研究不同阶段肾功能损害患者是否需要调整每日一次的人胰高血糖素样肽-1 类似物利拉鲁肽的剂量。
方法：30 名受试者组成队列，其中 24 名患有不同程度的肾功能损害，6 名肾功能正常，给予单次皮下注射利拉鲁肽 0.75mg，并进行连续采血以进行药代动力学估算的血浆利拉鲁肽测量。
结果：随着肾功能障碍程度的增加，各分组之间的药代动力学变化趋势不明显。虽然组间比较利拉鲁肽浓度-时间曲线下面积（AUC）没有显示等效性[估计比值 AUC（严重）/AUC（健康）0.73，90%置信区间（CI）0.57，0.94；AUC（持续非卧床腹膜透析）（CAPD）/AUC（健康）0.74，90%CI 0.56，0.97]，但对肾功能正常和轻度至重度肾功能损害的受试者的 log（AUC）进行回归分析表明，清除率降低对利拉鲁肽的药代动力学无显著影响。研究中两个肌酐清除率最低和最高的受试者的预期 AUC 比值估计为 0.88（95%CI 0.58，1.34）（NS）。肾功能损害程度似乎与不良反应风险增加无关。
结论：该研究表明，肾功能损害患者使用利拉鲁肽没有安全性问题。肾功能障碍未发现增加利拉鲁肽的暴露，2 型糖尿病伴肾功能损害患者应使用利拉鲁肽的标准治疗方案。然而，目前利拉鲁肽在轻度肾功能疾病以外的患者中的经验有限。
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