Oscillations of C-peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations.

Abstract

C-peptide should be continuously suppressed. However, increased postdosing C-peptide is not an uncommon phenomenon in euglycemic clamp studies involving healthy participants. This study aimed to determine the extent to which the postdosing C-peptide increases from the baseline that could affect the accuracy of glucodynamics in euglycemic clamp studies involving healthy subjects. First, 10 healthy males underwent a 10-h euglycemic clamp without exogenous insulin administration to obtain a reference interval (RI) for the ratio of C-peptide after 0min (CPt ) to baseline C-peptide (CP0 ). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CPt /CP0 : group A ([CPt /CP0 ]max >upper limit of RI), group B (1<[CPt /CP0 ]max ≤upper limit of RI), and group C ([CPt /CP0 ]max ≤1). The differences in basal and clamped blood glucose, CPt /CP0 , and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CPt and the accuracy of pharmacodynamics was analyzed. The RI of CPt /CP0 was 22.7%-152.1%; 1.5×baseline might be a ceiling for the increase in CPt under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (Pfor trend =0.033). The AUCGIR,0-10h in groups A, B, and C was 1983±650,1682±454, and 1479±440mg/kg (P=0.047), respectively, under comparable IAsp exposure. No intergroup difference was detected in clamped glucose, IAsp dose, or body mass index. In conclusion, postdosing C-peptide over 1.5× baseline indicates insufficient inhibition of endogenous insulin secretion, which could compromise the pharmacodynamics of insulin preparations.