The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

Abstract

This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.