Røge Rikke M, Klim Søren, Kristensen Niels R, Ingwersen Steen H, Kjellsson Maria C
Novo Nordisk A/S, Søborg, Denmark; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
J Clin Pharmacol. 2014 Jul;54(7):809-17. doi: 10.1002/jcph.270. Epub 2014 Mar 11.
Insulin therapy for diabetes patients is designed to mimic the endogenous insulin response of healthy subjects and thereby generate normal blood glucose levels. In order to control the blood glucose in insulin-treated diabetes patients, it is important to be able to predict the effect of exogenous insulin on blood glucose. A pharmacokinetic/pharmacodynamic model for glucose homoeostasis describing the effect of exogenous insulin would facilitate such prediction. Thus the aim of this work was to extend the previously developed integrated glucose-insulin (IGI) model to predict 24-hour glucose profiles for patients with Type 2 diabetes following exogenous insulin administration. Clinical data from two trials were included in the analysis. In both trials, 24-hour meal tolerance tests were used as the experimental setup, where exogenous insulin (biphasic insulin aspart) was administered in relation to meals. The IGI model was successfully extended to include the effect of exogenous insulin. Circadian variations in glucose homeostasis were assessed on relevant parameters, and a significant improvement was achieved by including a circadian rhythm on the endogenous glucose production in the model. The extended model is a useful tool for clinical trial simulation and for elucidating the effect profile of new insulin products.
糖尿病患者的胰岛素治疗旨在模拟健康受试者的内源性胰岛素反应，从而使血糖水平正常化。为了控制接受胰岛素治疗的糖尿病患者的血糖，能够预测外源性胰岛素对血糖的影响非常重要。描述外源性胰岛素作用的葡萄糖稳态药代动力学/药效学模型将有助于这种预测。因此，这项工作的目的是扩展先前开发的整合葡萄糖-胰岛素（IGI）模型，以预测2型糖尿病患者在外源性胰岛素给药后的24小时血糖曲线。分析纳入了两项试验的临床数据。在这两项试验中，均采用24小时进餐耐量试验作为实验设置，根据进餐情况给予外源性胰岛素（门冬双相胰岛素）。IGI模型成功扩展以纳入外源性胰岛素的作用。对相关参数评估了葡萄糖稳态的昼夜变化，通过在模型中纳入内源性葡萄糖生成的昼夜节律取得了显著改善。扩展模型是用于临床试验模拟和阐明新型胰岛素产品作用概况的有用工具。
