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).

How to Improve the Quality of Euglycemic Glucose Clamp Tests in Long-Acting Insulin Studies

“…20,21 Cpeptide has a long half-life and can re ect the secretion of endogenous insulin; therefore, it is frequently used to evaluate the index of endogenous insulin. Previous studies 22,23 have indicated that endogenous insulin inhibition is su cient if the C-peptide inhibition rate is > 50%. Therefore, we categorized the participants into two groups according to the C-peptide reduction ratio.…”

“…However, the reduction in the ratio of C-peptide in Group D (C-peptide reduction ≥ 50%) was signi cantly higher than that in Group C (C-peptide reduction < 50%), which is consistent with previous studies. [22][23][24] The process of the euglycemic clamp test is affected by various factors, such as the basal metabolic state of volunteers, basal glucose and insulin levels before injection of exogenous insulin, the dosage of insulin preparations, insulin sensitivity, and BG regulation during the euglycemic clamp test. 20,25 In this study, we screened healthy volunteers strictly according to the prede ned inclusion and exclusion criteria.…”

“…For PD blood sample collection, within the rst 10 h after drug administration (including 10 h), blood collection was performed every 15 min, every 10 min at 10-16 h (including 16 h) after administration, and every 20 min at 16-24 h (including 24 h) after administration. PK and C-peptide blood sample collection: 30 min before administration, 0.5 h after administration, and 1, 2, 4, 6, 7, 8, 10,11,12,13,15,16,18,20,22, and 24 h. The blood samples were collected from the forearm veins of the participants for PK and C-peptide detection.…”

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar insulin N with US‐licensed Humulin® N formulation in healthy subjects: Results from the RHINE‐2 (Recombinant Human INsulin Equivalence‐2) study

“…to identify variations of endogenous insulin secretion during the clamp procedure. 18 C-peptide-based correction methods were employed for primary analyses of PK and PD parameters to further rule out any impact of endogenous insulin on the PK or PD outcomes.…”

“…C‐peptide levels were determined, in parallel, to identify subjects whose endogenous insulin production may potentially interfere with insulin PK and PD measurements, i.e. to identify variations of endogenous insulin secretion during the clamp procedure 18 . C‐peptide‐based correction methods were employed for primary analyses of PK and PD parameters to further rule out any impact of endogenous insulin on the PK or PD outcomes.…”