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 0 min (CP_t ) 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 CP_t /CP₀ : group A ([CP_t /CP₀ ]_max > upper limit of RI), group B (1<[CP_t /CP₀ ]_max ≤ upper limit of RI), and group C ([CP_t /CP₀ ]_max ≤ 1). The differences in basal and clamped blood glucose, CP_t /CP₀ , and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CP_t and the accuracy of pharmacodynamics was analyzed. The RI of CP_t /CP₀ was 22.7%-152.1%; 1.5 × baseline might be a ceiling for the increase in CP_t under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (P_{for trend} = 0.033). The AUC_GIR,0-10h in groups A, B, and C was 1983 ± 650,1682 ± 454, and 1479 ± 440 mg/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.

Keywords: C-peptide; endogenous insulin; euglycemic clamp; pharmacodynamics.