Pharmacokinetics and pharmacodynamics of insulin lispro protamine suspension compared with insulin glargine and insulin detemir in type 2 diabetes
Pharmacokinetics and pharmacodynamics of insulin lispro protamine suspension compared with insulin glargine and insulin detemir in type 2 diabetes
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DOI：
10.1185/03007990903223739
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发表时间：
2009-11-01
影响因子：
2.3
通讯作者：
Jacober, Scott J.
中科院分区：
文献类型：
--
作者：
Hompesch, Marcus;Ocheltree, Scott M.;Jacober, Scott J.
目的：主要目的是评估单剂量 0.8 U/kg 赖脯胰岛素鱼精蛋白混悬液 (ILPS) 对 2 型糖尿病 (T2DM) 患者的作用持续时间；其次比较ILPS、甘精胰岛素(G)和地特胰岛素(D)(0.8 U/kg)的起效和作用持续时间，并评估ILPS的药代动力学(PK)和药效学(PD)剂量反应。 研究设计和方法：在一项单中心、双盲、五臂交叉研究中，34名患者被随机接受治疗序列，其中包括单次皮下注射0.8 U/kg剂量的G和D以及三剂ILPS （0.4 U/kg、0.8 U/kg 和 1.2 U/kg），并使用 24 小时正常血糖钳夹进行研究。主要结果测量：作用持续时间被确定为葡萄糖钳夹期间最后一次可测量的葡萄糖输注速率 (tR(last)) 的时间。结果：0.8 U/kg 的 ILPS 的胰岛素作用持续时间 (tR(last)) > 23 小时，与 G 相似(p = 0.114) 和 D (p = 0.570)。事后分析表明，0.8 U/kg 剂量后实现 24 小时降糖活性的概率为：48% (ILPS)、43% (G) 和 26% (D)。 ILPS 的 G(tot) 和 R-max 显着大于 G 或 D。中位 ILPS 时间依赖性值显示出与 G 或 D 相比显着更早的最大 PD 反应（tR(max) 和早期 50% tR(max)）。ILPS 在整个剂量范围内表现出 PK 和 PD 测量值的剂量依赖性增加。结论：在 T2DM 患者中单次 0.8 U/kg 剂量后，ILPS、G 和 D 表现出相似的 PD 反应持续时间。降糖活性和 ILPS 表现出显着更高的降糖活性（R-max 和 G(tot)）和更早的最大 PD 反应。这些结果可能支持 T2DM 每日一次服用 ILPS。 局限性：24 小时审查观察的观察数量高于预期，基础胰岛素治疗患者的清除期可能太短，无法明确排除残留效应；然而，这种效应如果存在，可能只会影响行动的开始，而不影响主要结果指标。
Objective:The primary aim was to evaluate duration of action of a single 0.8 U/kg dose of insulin lispro protamine suspension (ILPS) in type 2 diabetes (T2DM) patients; secondarily to compare onset and duration of action of ILPS, glargine (G), and detemir (D) (0.8 U/kg) and evaluate pharmacokinetic (PK) and pharmacodynamic (PD) dose responses of ILPS.Research design and methods:In a single-center, double-blind, five-arm crossover study, 34 patients were randomized to a treatment sequence which included a single subcutaneous 0.8 U/kg dose of G and D and three doses of ILPS (0.4 U/kg, 0.8 U/kg, and 1.2 U/kg) and were studied using 24-hour euglycemic glucose clamps.Primary outcome measure:Duration of action was determined as the time to the last measurable glucose infusion rate (tR(last)) during glucose clamps.Results:The duration of insulin action (tR(last)) for ILPS at 0.8 U/kg was >23 hours and was similar to G (p = 0.114) and D (p = 0.570). Post-hoc analysis demonstrated the probability of achieving 24 hours of glucose-lowering activity after a 0.8 U/kg dose: 48% (ILPS), 43% (G), and 26% (D). G(tot) and R-max were significantly greater for ILPS versus G or D. The median ILPS time-dependent values demonstrated a significantly earlier maximum PD response (tR(max) and early 50% tR(max)) versus either G or D. ILPS demonstrated dose-dependent increases in PK and PD measures across the dose range.Conclusions:Following a single 0.8 U/kg dose in T2DM patients, ILPS, G, and D demonstrated similar durations of glucose-lowering activity and ILPS demonstrated significantly greater glucose-lowering activity (R-max and G(tot)) and earlier maximum PD response. These results potentially support once-daily dosing of ILPS in T2DM.Limitations:The observed number of 24-hour censored observations was higher than expected and the wash-out period for basal insulin treated patients may have been too short to definitively rule out a carry-over effect; however, such an effect, if present, would potentially only affect onset of action and not the primary outcome measure.