Dataset Information

How to Achieve Sufficient Endogenous Insulin Suppression in Euglycemic Clamps Assessing the Pharmacokinetics and Pharmacodynamics of Long-Acting Insulin Preparations Employing Healthy Volunteers.

ABSTRACT: The therapeutic effect of basal insulin analogs will be sustained at a rather low insulin level. When employing healthy volunteers to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of long-acting insulin preparations by euglycemic clamp techniques, endogenous insulin cannot be ignored and sufficient endogenous insulin inhibition is crucial for the PD and/or PK assessment. This study aimed to explore a way to sufficiently inhibit endogenous insulin secretion. Healthy Chinese male and female volunteers were enrolled. After a subcutaneous injection of insulin glargine (IGlar) (LY2963016 or Lantus) (0.5 IU/kg), they underwent a manual euglycemic clamp for up to 24 h where the target blood glucose (BG) was set as 0.28 mmol/L below the individual's baseline. Blood samples were collected for analysis of PK/PD and C-peptide. The subjects fell into two groups according to the reduction extent of postdose C-peptide from baseline. After matching for the dosage proportion of Lantus, there were 52 subjects in group A (C-peptide reduction<50%) and 26 in group B (C-peptide reduction≥50%), respectively. No significant difference was detected in age, body mass index, the proportion of Latus treatment and female participants. A lower basal BG was observed in group B compared to group A (4.35 ± 0.26 vs. 4.59 ± 0.22 mmol/L, p < 0.05). The clamp studies were all conducted with high quality (where BG was consistently maintained around the target and exhibited a low variety). The binary logistic regression analysis indicated low basal BG as an independent factor for the success of sufficient endogenous insulin suppression. In conclusion, setting a lower sub-baseline target BG (e.g., 10% instead of 5% below baseline) might be an approach to help achieve sufficient endogenous insulin suppression in euglycemic clamps with higher basal BG levels (e.g., beyond 4.60 mmol/L).

SUBMITTER: Liu H

PROVIDER: S-EPMC9354408 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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How to Achieve Sufficient Endogenous Insulin Suppression in Euglycemic Clamps Assessing the Pharmacokinetics and Pharmacodynamics of Long-Acting Insulin Preparations Employing Healthy Volunteers.

Liu Hui H Li Ting T Yu Hongling H Li Jiaqi J Tan Huiwen H Yu Yerong Y

Frontiers in pharmacology 20220722

The therapeutic effect of basal insulin analogs will be sustained at a rather low insulin level. When employing healthy volunteers to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of long-acting insulin preparations by euglycemic clamp techniques, endogenous insulin cannot be ignored and sufficient endogenous insulin inhibition is crucial for the PD and/or PK assessment. This study aimed to explore a way to sufficiently inhibit endogenous insulin secretion. Healthy Chinese male and ...[more]

PMID: 35935883

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Project description:BackgroundThe euglycemic clamp test stands as the best method for assessing the pharmacokinetic and pharmacodynamic properties of long-acting insulin. However, despite its widespread use, there remains a notable absence of an established gold standard for evaluating the test's quality. Existing recommendations from regulatory agencies lack specific threshold values, particularly concerning long-acting insulin. This study aimed to determine the evaluation criteria for assessing the quality of the long-acting insulin euglycemic glucose clamp test and to improve the overall quality of this testing method.MethodsFifty-three healthy volunteers were administered a single dose of insulin degludec (0.4 IU/kg) and underwent a 24-h euglycemic clamp test. Blood samples were collected to evaluate the pharmacokinetics and pharmacodynamics of insulin degludec. Volunteers were separated into group A (coefficient of variation in blood glucose [CVBG] ≤ 3.5%) and group B (CVBG > 3.5%). The quality difference of the clamp test between the groups was assessed using various quality control indices. Volunteers were also categorized into group C (C-peptide reduction rate < 50%) and group D (C-peptide reduction rate ≥ 50%). The clamp test quality, pharmacokinetics, and pharmacodynamics of groups C and D were compared.ResultsAccording to CVBG, group A had a mean CVBG of 2.95%, group B had a mean CVBG of 4.15%, and group A had a significantly lower CVBG than group B (p < 0.001). CVBG was positively correlated with other quality control indicators, such as the percentage of glucose excursion from the target range (GEFTR), duration of GEFTR, and area under the curve (AUC) of GEFTR. According to the reduction of C-peptide levels: group D had significantly higher C-peptide reduction than group C (p < 0.001). Groups C and D had CVBG < 3.5%. The quality of groups C and groups D was evaluated by the quality control indicators of the clamp test. Only the AUC of GEFTR was statistically different between Groups C and D (p = 0.043, < 0.05), and there was no statistical difference in other indicators between the two groups.ConclusionsCVBG could be used as a standard for evaluating the quality of long-acting insulin euglycemic glucose clamp test, and the test quality was superior with a CVBG ≤ 3.5%. A C-peptide reduction ratio ≥ 50% indicated sufficient endogenous insulin inhibition; however, when the glucose fluctuation is small (CVBG is maintained at a low level) during the clamp test, even if the clamp test quality is slightly different, it is not sufficient to interfere with endogenous insulin secretion.

Dataset Information

How to Achieve Sufficient Endogenous Insulin Suppression in Euglycemic Clamps Assessing the Pharmacokinetics and Pharmacodynamics of Long-Acting Insulin Preparations Employing Healthy Volunteers.

Publications

How to Achieve Sufficient Endogenous Insulin Suppression in Euglycemic Clamps Assessing the Pharmacokinetics and Pharmacodynamics of Long-Acting Insulin Preparations Employing Healthy Volunteers.

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