肾功能对健康受试者和 2 型糖尿病患者中达格列净暴露、代谢和药效学的影响。
The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus.
机构信息
Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Co, Princeton, NJ.
出版信息
Br J Clin Pharmacol. 2013 Sep;76(3):432-44. doi: 10.1111/bcp.12056.
AIM(S): This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM).
METHODS
A single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20 mg once daily multiple doses of dapagliflozin were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using human isolated kidney and liver microsomes.
RESULTS
Plasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate and severe renal impairment, respectively, compared with normal function. AUC(0,τ) was likewise higher. D3OG formation in kidney microsomes was three-fold higher than in liver microsomes and 109-fold higher than in intestine microsomes. Compared with patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83% and 84% in patients with mild, moderate or severe renal impairment, respectively.
CONCLUSIONS
These results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.
目的
本研究评估了肾功能差异对达格列净（一种用于治疗 2 型糖尿病（T2DM）的肾脏钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂）药代动力学和药效学的影响。
方法
使用单次 50mg 剂量的达格列净评估了 5 组人群的药代动力学和药效学：健康非糖尿病受试者；肾功能正常的 T2DM 患者和根据估算肌酐清除率有轻度、中度或重度肾功能损害的 T2DM 患者。随后，评估了 20mg 每日一次多次剂量的达格列净在 T2DM 患者中的情况。使用人离体肾脏和肝脏微粒体评估达格列净 3-O-葡萄糖醛酸（D3OG），一种无活性代谢物的形成率。
结果
随着肾功能的下降，达格列净和 D3OG 的血浆浓度逐渐升高。与肾功能正常的患者相比，轻度、中度和重度肾功能损害的患者达格列净的稳态 Cmax 分别升高了 4%、6%和 9%，D3OG 分别升高了 20%、37%和 52%；AUC（0，τ）也更高。肾脏微粒体中 D3OG 的形成是肝脏微粒体的三倍，是肠微粒体的 109 倍。与肾功能正常的患者相比，肾功能损害会使药效减弱。轻度、中度和重度肾功能损害的患者稳态肾葡萄糖清除率分别降低了 42%、83%和 84%。
结论
这些结果表明，肾脏和肝脏均显著参与达格列净的代谢，导致随着肾功能下降而出现更高的全身暴露。在肾功能中度至重度受损的糖尿病患者中，达格列净的药效学与该患者人群中疗效降低的观察结果一致。
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