Apidra Mechanism of Action

Pharmacotherapeutic group: Drugs used in diabetes, insulin and analogues for injection, fast-acting. ATC code: A10AB06.
Pharmacology: Pharmacodynamics: Mechanism of action: Insulin glulisine is a recombinant human insulin analogue that is equipotent to regular human insulin. Insulin glulisine has a more rapid onset of action and a shorter duration of action than regular human insulin.
The primary activity of insulins and insulin analogues, including insulin glulisine, is regulation of glucose metabolism. Insulins 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. Studies in healthy volunteers and patients with diabetes demonstrated that insulin glulisine is more rapid in onset of action and of shorter duration of action than regular human insulin when given subcutaneously. When insulin glulisine is injected subcutaneously, the glucose lowering activity will begin within 10 - 20 minutes. The glucose-lowering activities of insulin glulisine and regular human insulin are equipotent when administered by intravenous route. One unit of insulin glulisine has the same glucose-lowering activity as one unit of regular human insulin.
Dose proportionality: In a study with 18 male subjects with diabetes mellitus type 1 aged 21 to 50 years, insulin glulisine displayed dose-proportional glucose lowering effect in the therapeutic relevant dose range 0.075 to 0.15 Units/kg, and less than proportional increase in glucose lowering effect with 0.3 Units/kg or higher, like human insulin.
Insulin glulisine takes effect about twice as fast as regular human insulin and completes the glucose lowering effect about 2 hours earlier than regular human insulin.
A phase I study in patients with type 1 diabetes mellitus assessed the glucose lowering profiles of insulin glulisine and regular human insulin administered subcutaneously at a dose of 0.15 Units/kg, at different times in relation to a 15-minute standard meal. Data indicated that insulin glulisine administered 2 minutes before the meal gives similar postprandial glycemic control compared to regular human insulin given 30 minutes before the meal. When given 2 minutes prior to meal, insulin glulisine provided better postprandial control than regular human insulin given 2 minutes before the meal. Insulin glulisine administered 15 minutes after starting the meal gives similar glycemic control as regular human insulin given 2 minutes before the meal (see Figure 1).

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Obesity: A phase I study carried out with insulin glulisine, lispro and regular human insulin in an obese population has demonstrated that insulin glulisine maintains its rapid-acting properties. In this study, the time to 20% of total AUC and the AUC (0-2h) representing the early glucose lowering activity were respectively of 114 minutes and 427mg.kg-1 for insulin glulisine, 121 minutes and 354mg.kg-1 for lispro, 150 minutes and 197mg.kg-1 for regular human insulin (see Figure 2).

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Another phase 1 study with insulin glulisine and insulin lispro in a non-diabetic population in 80 subjects with a wide range of body mass indices (18-46kg/m²) has demonstrated that rapid action is generally maintained across a wide range of body mass indices, while total glucose lowering effect decreases with increasing obesity.
The average total GIR AUC between 0-1 hour was 102±75 mg/kg and 158±100 mg/kg with 0.2 and 0.4 Units/kg insulin glulisine, respectively, and was 83.1±72.8 mg/kg and 112.3±70.8 mg/kg with 0.2 and 0.4 Units/kg insulin lispro respectively.
A phase I study in 18 obese patients with type 2 diabetes mellitus (BMI between 35 and 40 kg/m²) with insulin glulisine and insulin lispro [90% CI: 0.81, 0.95 (p=<0.01)] has shown that insulin glulisine more effectively controls diurnal post-prandial blood glucose excursions.
Clinical efficacy and safety: Type 1 diabetes mellitus - Adults: In a 26-week phase III clinical study comparing insulin glulisine with insulin lispro both injected subcutaneously shortly (0-15 minutes) before a meal in patients with type 1 diabetes mellitus using insulin glargine as basal insulin, insulin glulisine was comparable to insulin lispro for glycemic control as reflected by changes in glycated haemoglobin (expressed as HbA1c equivalent) from baseline to endpoint. Comparable self-monitored blood glucose values were observed. No increase in the basal insulin dose was needed with insulin glulisine, in contrast to insulin lispro.
A 12-week phase III clinical study performed in patients with type 1 diabetes mellitus receiving insulin glargine as basal therapy indicate that the immediate post-meal administration of insulin glulisine provides efficacy that was comparable to immediate pre-meal insulin glulisine (0-15 minutes) or regular insulin (30-45 minutes).
In the per protocol population there was a significantly larger observed reduction in GHb in the pre-meal glulisine group compared with the regular insulin group.
Type 1 diabetes mellitus - Paediatric: In a 26-week phase III clinical study comparing insulin glulisine with insulin lispro both injected subcutaneously shortly (0-15 minutes) before a meal in children (4-5 years: n=9; 6-7 years: n=32 and 8-11 years: n=149) and adolescents (12-17 years: n=382) with type 1 diabetes mellitus using insulin glargine or NPH as basal insulin. Insulin glulisine was comparable to insulin lispro for glycemic control as reflected by changes in glycated haemoglobin (GHb expressed as HbA1c equivalent) from baseline to endpoint and by self-monitored blood glucose values.
There is insufficient clinical information on the use of Apidra in children younger than the age of 6 years.
Type 2 diabetes mellitus - Adults: A 26-week phase III clinical study followed by a 26-week extension safety study was conducted to compare insulin glulisine (0-15 minutes before a meal) with regular human insulin (30-45 minutes before a meal) injected subcutaneously in patients with type 2 diabetes mellitus also using NPH insulin as basal insulin. The average body mass index (BMI) of patients was 34.55 kg/m2. Insulin glulisine was shown to be comparable to regular human insulin with regard to glycated haemoglobin (expressed as HbA1c equivalent) changes from baseline to the 6-month endpoint (-0.46% for insulin glulisine and -0.30% for regular human insulin, p=0.0029) and from baseline to the 12-month endpoint (-0.23% for insulin glulisine and -0.13% for regular human insulin, difference not significant). In this study, the majority of patients (79%) mixed their short acting insulin with NPH insulin immediately prior to injection and 58% of subjects used oral hypoglycemic agents at randomization and were instructed to continue to use them at the same dose.
Race and Gender: In controlled clinical trials in adults, insulin glulisine did not show differences in safety and efficacy in subgroup analyses based on race and gender.
Pharmacokinetics: In insulin glulisine the replacement of the human insulin amino acid asparagine in position B3 by lysine and the lysine in position B29 by glutamic acid favors more rapid absorption.
In a study with 18 male subjects with diabetes mellitus type 1, aged 21 to 50 years, insulin glulisine displays dose-proportionality for early, maximum and total exposure in the dose range 0.075 to 0.4 Units/kg.
Absorption and bioavailability: Pharmacokinetic profiles in healthy volunteers and diabetes patients (type 1 or 2) demonstrated that absorption of insulin glulisine was about twice as fast with a peak concentration approximately twice as high as compared to regular human insulin.
In a study in patients with type 1 diabetes mellitus after subcutaneous administration of 0.15 Units/kg, for insulin glulisine the Tmax was 55 minutes and Cmax was 82 ± 1.3 μUnits/ml compared to a Tmax of 82 minutes and a Cmax of 46 ± 1.3 μU/ml for regular human insulin. The mean residence time of insulin glulisine was shorter (98 min) than for regular human insulin (161 min) (see Figure 3).

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In a study in patients with type 2 diabetes mellitus after subcutaneous administration of 0.2 Units/kg insulin glulisine, the Cmax was 91 μUnits/ml with the interquartile range from 78 to 104 μUnits/ml.
When insulin glulisine was injected subcutaneously into abdomen, deltoid and thigh, the concentration-time profiles were similar with a slightly faster absorption when administered in the abdomen compared to the thigh. Absorption from deltoid sites was in-between (see Dosage & Administration). The absolute bioavailability (70%) of insulin glulisine was similar between injection sites and of low intra-subject variability (11% CV).
Obesity: Another phase 1 study with insulin glulisine and insulin lispro in a non-diabetic population in 80 subjects with a wide range of body mass indices (18-46 kg/ml²) has demonstrated that rapid absorption and total exposure is generally maintained across a wide range of body mass indices.
The time to 10% of total INS exposure was reached earlier by approximately 5-6 min with insulin glulisine.
Distribution and elimination: The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration is similar with volumes of distribution of 13 l and 22 l and half-lives of 13 and 18 minutes, respectively.
After subcutaneous administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86 minutes. In an across study analysis of insulin glulisine in either healthy subjects or subjects with type 1 or type 2 diabetes mellitus the apparent half-life ranged from 37 to 75 minutes (interquartile range).
Insulin glulisine shows low plasma protein binding, similar to human insulin.
Special populations: Renal impairment: In a clinical study performed in non-diabetic subjects covering a wide range of renal function (CrCl > 80 ml/min, 30-50 ml/min, <30 ml/min), the rapid-acting properties of insulin glulisine were generally maintained. However, insulin requirements may be reduced in the presence of renal impairment.
Hepatic impairment: The pharmacokinetic properties have not been investigated in patients with impaired liver function.
Elderly: Very limited pharmacokinetic data are available for elderly patients with diabetes mellitus.
Children and adolescents: The pharmacokinetic and pharmacodynamic properties of insulin glulisine were investigated in children (7-11 years) and adolescents (12-16 years) with type 1 diabetes mellitus. Insulin glulisine was rapidly absorbed in both age groups, with similar Tmax and Cmax as in adults (see Dosage & Administration).
Administered immediately before a test meal, insulin glulisine provided better postprandial control than regular human insulin, as in adults (see Pharmacodynamics as previously mentioned). The glucose excursion (AUC_0-6h) was 641mg·h·dl^-1 for insulin glulisine and 801mg·h·dl^-1 for regular human insulin.
Toxicology: Preclinical safety data: Non-clinical data did not reveal toxicity findings others than those linked to the blood glucose lowering pharmacodynamic activity (hypoglycemia), different from regular human insulin or of clinical relevance for humans.