A new C‐peptide correction model used to assess bioavailability of regular human insulin

Abstract

The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.

Effects of Unsuppressed Endogenous Insulin on Pharmacokinetics and/or Pharmacodynamics of Study Insulin in the Healthy: A Retrospective Study

“…In studies in which specific assays for the tested insulin are lacking, C-peptide was always used to correct endogenous insulin. 37,38 Some researchers 39 still doubted the use of C-peptide to correct endogenous insulin because some PK parameters were not consistent (eg, a peak of glargine in plasma occurring at 12 hours 40 differs from those observed in subjects with type 1 diabetes where the increase occurs between ≈3 and 6 hours after the first injection 41 and at steady state 42 ). Owens 19 reported the exogenous insulin estimated from C-peptide was nearly the same as what was true when C-peptide was well inhibited.…”

An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin

“…A phase 1, single-center, open-label, randomized, crossover study in 21 healthy subjects (who provided written informed consent) was conducted upon approval of the institutional ethics committee (protocol number MKC-TI-141) and following the principles of the Declaration of Helsinki 14 . In summary, all subjects underwent two equivalent standardized meal tests (approximately 600 kcal to be completed within 20 min) on separate days after overnight fasting, with one of the tests preceded by inhalation of a dose (22U or 20U) of Technosphere ® Insulin through the Gen2B Inhaler.…”

“…The dynamic model-based method for estimating endogenous plasma insulin proposed herein was compared to the “C-peptide correction” methods previously proposed by Owens 13 and by Marino et al 14 These latter two methods attempt to correct the measured insulin concentration by removing the component (assumed constant) attributable to endogenous secretion, thus resulting in the isolated contribution of exogenous insulin.…”

“…Baseline correction, however, represents a very rough quantification as it does not reflect the dynamic changes during the test. Some attempts to provide a more refined correction based on C-peptide were made that involve mixed effects regression equations 14 but such black box data-driven approaches disregard the description of the underlying physiological processes; moreover, robustness of such approaches in individual estimation are strongly affected by statistical assumptions including the choice of covariates 15 .…”

Assessing Islet Function Using 2-h Postprandial C Peptide in Type 2 Diabetes Mellitus

“…The islet molecules secrete insulin and C-peptide. Some studies have shown that C-peptide can be used to guide the clinical treatment of diabetes (3,4) and postprandial C-peptide could reflect the patient's islet reserve function (5). Short-term intensive insulin therapy could induce remission in some newly diagnosed Type 2 diabetes mellitus (T2DM) patients (6-10); however, not all patients are suitable for intensive treatment, and its clinical application still lacks effective indicators.…”