Population pharmacodynamic modeling of hyperglycemic clamp and meal tolerance tests in patients with type 2 diabetes mellitus

In this study, glucose and insulin concentration-time 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 4 weeks and then switched to the alternative treatment after a 4-week washout period. The MTT and HGC tests were performed 1 h 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 62.5 min. 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 0.164 L/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. 0.00425 L/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 glucose-insulin homeostasis.