Population Pharmacodynamic Modeling of Hyperglycemic Clamp and Meal Tolerance Tests in Patients with Type 2 Diabetes Mellitus

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• 作者：Ying Hong (1)
  Jasper Dingemanse (2)
  Patricia Sidharta (2)
  Donald E. Mager (1)
  
• 关键词：hyperglycemic clamp ; meal tolerance test ; pharmacodynamic modeling ; type 2 diabetes mellitus
• 刊名：The AAPS Journal
• 出版年：2013
• 出版时间：October 2013
• 年：2013
• 卷：15
• 期：4
• 页码：1051-1063
• 全文大小：
• 作者单位：Ying Hong (1)
  Jasper Dingemanse (2)
  Patricia Sidharta (2)
  Donald E. Mager (1)
  
  1. Department of Pharmaceutical Sciences, University at Buffalo, SUNY, 431 Kapoor Hall, Buffalo, New York, 14214, USA
  2. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
  
• ISSN：1550-7416

文摘

In this study, glucose and insulin concentrationime profiles in subjects with type 2 diabetes mellitus (T2DM) under meal tolerance test (MTT) and hyperglycemic clamp (HGC) conditions were co-modeled simultaneously. Blood glucose and insulin concentrations were obtained from 20 subjects enrolled in a double-blind, placebo-controlled, randomized, two-way crossover study. Patients were treated with palosuran or placebo twice daily for 4weeks and then switched to the alternative treatment after a 4-week washout period. The MTT and HGC tests were performed 1h after drug administration on days 28 and 29 of each treatment period. Population data analysis was performed using NONMEM. The HGC model incorporates insulin-dependent glucose clearance and glucose-induced insulin secretion. This model was extended for the MTT, in which glucose absorption was described using a transit compartment with a mean transit time of 62.5min. The incretin effect (insulin secretion triggered by oral glucose intake) was also included, but palosuran did not influence insulin secretion or sensitivity. Glucose clearance was 0.164L/min with intersubject and interoccasion variability of 9.57% and 31.8%. Insulin-dependent glucose clearance for the HGC was about 3-fold greater than for the MTT (0.0111 vs. 0.00425L/min/[mU/L]). The maximal incretin effect was estimated to enhance insulin secretion 2-fold. The lack of palosuran effect coupled with a population-based analysis provided quantitative insights into the variability of glucose and insulin regulation in patients with T2DM following multiple glucose tolerance tests. Application of these models may also prove useful in antihyperglycemic drug development and assessing glucosensulin homeostasis.