Chemical formula: C₂₆₇H₄₀₄N₇₂O₇₈S₆ Molecular mass: 6,060.825 g/mol
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.
Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. At pH 4, insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralised leading to formation of a precipitate from which small amounts of insulin glargine are continuously released.
Insulin glargine is metabolised into 2 active metabolites M1 and M2.
Insulin receptor binding: In vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for the human insulin receptor is similar to the one of human insulin.
IGF-1 receptor binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately 5 to 8-fold greater than that of human insulin (but approximately 70 to 80-fold lower than the one of IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to human insulin.
The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than what would be required for a half maximal occupation of the IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated by the IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy are considerably lower than the pharmacological concentrations required to activate the IGF-1 pathway.
In a clinical pharmacology study, intravenous insulin glargine and human insulin have been shown to be equipotent when given at the same doses.
As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.
In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower and more prolonged absorption resulting in a flatter time-concentration profile after subcutaneous injection of insulin glargine in comparison to insulin glargine 100 units/ml.
Pharmacokinetic profiles were consistent with the pharmacodynamic activity of insulin glargine.
Steady state level within the therapeutic range is reached after 3-4 days of daily insulin glargine administration.
After subcutaneous injection of insulin glargine, the intra-subject variability, defined as the coefficient of variation for the insulin exposure during 24 hours was low at steady state (17.4%).
After subcutaneous injection of insulin glargine, insulin glargine is rapidly metabolized at the carboxyl terminus of the Beta chain with formation of two active metabolites M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the principal circulating compound is the metabolite M1.
The exposure to M1 increases with the administered dose of insulin glargine. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with insulin glargine is principally based on exposure to M1. Insulin glargine and the metabolite M2 were not detectable in the vast majority of subjects and, when they were detectable their concentration was independent of the administered dose and formulation of insulin glargine.
When given intravenously the elimination half-life of insulin glargine and human insulin were comparable.
The half-life after subcutaneous administration of insulin glargine is determined by the rate of absorption from the subcutaneous tissue. The half-life of insulin glargine after subcutaneous injection is 18-19 hours independent of dose.
Population pharmacokinetic analysis was conducted for insulin glargine based on concentration data of its main metabolite M1 using data from 75 pediatric subjects (6 to <18 years of age) with type 1 diabetes. Body weight affects the clearance of insulin glargine in a nonlinear way. As a consequence, exposure (AUC) in pediatric patients is slightly lower as compared to adult patients when receiving the same body weight adjusted dose.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
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