Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including insulin detemir, exert their specific action through binding to insulin receptors.
Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.
Insulin detemir is a soluble, long-acting basal human insulin analog with a relatively flat action profile. The mean duration of action of insulin detemir ranged from 5.7 hours at the lowest dose to 23.2 hours at the highest dose (sampling period 24 hours).
The prolonged action of LEVEMIR is mediated by the slow systemic absorption of insulin detemir molecules from the injection site due to strong self-association of the drug molecules and albumin binding. Insulin detemir is distributed more slowly to peripheral target tissues since insulin detemir in the bloodstream is highly bound to albumin.
Figure 1 shows glucose infusion rate results from a glucose clamp study in patients with type 1 diabetes.
Figure 1: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study
Figure 2 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2 diabetes. The clamp study was terminated at 16 hours according to protocol.
Figure 2: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study
For doses in the interval of 0.2 to 0.4 U/kg, LEVEMIR exerts more than 50% of its maximum effect from 3 to 4 hours up to approximately 14 hours after dose administration.
In a glucose clamp study, the overall glucodynamic effect (AUCGIR 0-24h) [mean mg/kg ± SD (CV)] of four separate subcutaneous injections in the thigh was 1702.6 ± 489 mg/kg (29%) in the LEVEMIR group and 1922.8 ± 765 mg/kg (40%) for NPH. The clinical significance of this difference has not been established.
After subcutaneous injection of insulin detemir in healthy subjects and in patients with diabetes, insulin detemir serum concentrations indicated a slower, more prolonged absorption over 24 hours in comparison to NPH human insulin.
Maximum serum concentration (Cmax) is reached between 6 and 8 hours after administration.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% insulin detemir in the bloodstream is bound to albumin. LEVEMIR has a small apparent volume of distribution of approximately 0.1 L/kg. LEVEMIR, after subcutaneous administration, has a terminal half-life of 5 to7 hours depending on dose.
Children and Adolescents - The pharmacokinetic properties of LEVEMIR were investigated in children (6 to 12 years) and adolescents (13 to 17 years) and adults with type 1 diabetes. Similar to NPH human insulin, slightly higher plasma Area Under the Curve (AUC) and Cmax were observed in children by 10% and 24%, respectively, compared to adolescents and adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics - In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose of LEVEMIR in young (25 to 35 years) versus elderly (≥68 years) healthy subjects, higher insulin AUC levels (up to 35%) were found in elderly subjects due to a reduced clearance. As with other insulin preparations, LEVEMIR should always be titrated according to individual requirements.
Gender - In controlled clinical trials, no clinically relevant difference between genders is seen in pharmacokinetic parameters based on subgroup analyses.
Race - In two trials in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. Pharmacokinetics and pharmacodynamics of LEVEMIR were investigated in a clamp trial comparing patients with type 2 diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships were comparable for LEVEMIR in these three populations.
Renal impairment - Individuals with renal impairment showed no difference in pharmacokinetic parameters as compared to healthy volunteers. However, literature reports have shown that clearance of human insulin is decreased in renally impaired patients. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).
Hepatic impairment - Individuals with severe hepatic dysfunction, without diabetes, were observed to have lower AUCs as compared to healthy volunteers. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).
Pregnancy - The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied (see PRECAUTIONS, Pregnancy).
Smoking - The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied.