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Oscillations of C‐peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations
Author(s) -
Liu Hui,
Yu Hongling,
Qiao Jingtao,
Sun Lisi,
Li Jiaqi,
Tan Huiwen,
Yu Yerong
Publication year - 2021
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12628
Subject(s) - pharmacodynamics , pharmacokinetics , insulin , glucose clamp technique , clamp , medicine , endocrinology , peptide , c peptide , basal (medicine) , insulin aspart , pharmacology , insulin resistance , chemistry , pancreatic hormone , postprandial , biochemistry , mechanical engineering , clamping , engineering
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 (CP 0 ). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CP t /CP 0 : group A ([CP t /CP 0 ] max > upper limit of RI), group B (1<[CP t /CP 0 ] max ≤ upper limit of RI), and group C ([CP t /CP 0 ] max ≤ 1). The differences in basal and clamped blood glucose, CP t /CP 0 , 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 /CP 0 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.