Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
Drug Metab Pharmacokinet. 2010;25(5):418-29. doi: 10.2133/dmpk.dmpk-10-rg-017. Epub 2010 Sep 30.
The pharmacokinetics and pharmacodynamics (PK/PD) of inhaled insulin in humans have not been modeled previously. We rationalized a model for the effects of inhaled insulin on glucose infusion rate during a euglycemic clamp study based on the mechanism of insulin action and compared parameter estimates between subcutaneous and inhaled insulin in healthy and diabetic subjects. Published data from two studies in 11 healthy volunteers and 18 type 1 diabetes patients were digitized. The subjects received four different doses of inhaled insulin and one or three different doses subcutaneously at the start of a 10 h glucose clamp. All data were modeled simultaneously using NONMEM VI. Insulin pharmacokinetics were described by a one-compartment model with one (inhaled) or two (subcutaneous insulin) first-order absorption processes and first-order elimination. Insulin effects on glucose were described by an indirect response model. A biophase direct effect equation for the glucose infusion rate was implemented. Pharmacodynamic parameter estimates were 15.1 mg/min/kg for maximal glucose infusion rate (GIR(max)) and 88.0 mIU/L for SC(50) for diabetic patients and 62.9 mIU/L for healthy subjects. A PK/PD model based on fundamental principles of insulin action and glucose turnover suggests comparable potencies of inhaled and subcutaneous insulin.
在人类中，吸入性胰岛素的药代动力学和药效学（PK/PD）以前尚未建模。我们基于胰岛素作用的机制，为吸入性胰岛素对正常血糖钳夹研究中葡萄糖输注率的影响建立了一个模型，并比较了健康和糖尿病受试者中皮下和吸入性胰岛素的参数估计值。从 11 名健康志愿者和 18 名 1 型糖尿病患者的两项研究中获取已发表的数据并进行数字化。受试者在 10 小时的葡萄糖钳夹开始时接受了四种不同剂量的吸入性胰岛素和一种或三种不同剂量的皮下胰岛素。使用 NONMEM VI 同时对所有数据进行建模。胰岛素药代动力学采用一室模型描述，具有一个（吸入）或两个（皮下胰岛素）一级吸收过程和一级消除过程。胰岛素对葡萄糖的作用通过间接反应模型进行描述。实施了用于葡萄糖输注率的双相直接效应方程。药效学参数估计值为：糖尿病患者的最大葡萄糖输注率（GIR(max)）为 15.1 mg/min/kg，SC(50)为 88.0 mIU/L，健康受试者为 62.9 mIU/L。基于胰岛素作用和葡萄糖周转的基本原理的 PK/PD 模型表明，吸入性胰岛素和皮下胰岛素的效能相当。
