Insulin detemir

Insulin detemir is a soluble, long-acting insulin analogue with a prolonged duration of effect used as a basal insulin.

The blood glucose lowering effect of insulin detemir is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.

The time action profile of insulin detemir is statistically significantly less variable and therefore more predictable than for NPH (Neutral Protamine Hagedorn) insulin as seen from the within-subject Coefficients of Variation (CV) for the total and maximum pharmacodynamic effect in Table 1.

Table 1. Within-subject variability of the time action profile of insulin detemir and NPH insulin:

* Area under the curve
** Glucose Infusion Rate p-value <0.001 for all comparisons with insulin detemir

The prolonged action of insulin detemir is mediated by the strong self-association of insulin detemir molecules at the injection site and albumin binding via the fatty acid side-chain. Insulin detemir is distributed more slowly to peripheral target tissues compared to NPH insulin. These combined mechanisms of protraction provide a more reproducible absorption and action profile of insulin detemir compared to NPH insulin.

Absorption

Maximum serum concentration is reached between 6 and 8 hours after administration. When administered twice daily, steady state serum concentrations are reached after 2–3 dose administrations. Within-patient variation in absorption is lower for insulin detemir than for other basal insulin preparations. The absolute bioavailability of insulin detemir when administered subcutaneous is approximately 60%.

Distribution

An apparent volume of distribution for insulin detemir (approximately 0.1 l/kg) indicates that a high fraction of insulin detemir is circulating in the blood. The results of the in vitro and in vivo protein binding studies suggest that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein bound medicinal products.

Biotransformation

Degradation of insulin detemir is similar to that of human insulin; all metabolites formed are inactive.

Elimination

The terminal half-life after subcutaneous administration is determined by the rate of absorption from the subcutaneous tissue. The terminal half-life is between 5 and 7 hours depending on the dose.

Linearity

Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after subcutaneous administration in the therapeutic dose range.

No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and insulin detemir when administering a single dose of insulin detemir 0.5 units/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.

Special populations

Elderly (≥65 years old)

There was no clinically relevant difference in pharmacokinetics of insulin detemir between elderly and young patients.

Renal and hepatic impairment

There was no clinically relevant difference in pharmacokinetics of insulin detemir between patients with renal or hepatic impairment and healthy subjects. As the pharmacokinetics of insulin detemir has not been studied extensively in these populations, it is advised to monitor plasma glucose closely in these populations.

Gender

There are no clinically relevant differences between genders in pharmacokinetic properties of insulin detemir.

Paediatric population

The pharmacokinetic properties of insulin detemir were investigated in young children (1–5 years), children (6–12 years) and adolescents (13–17 years) and compared to adults with type 1 diabetes. There were no clinically relevant differences in pharmacokinetic properties between young children, children, adolescents and adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. Receptor affinity data and in vitro mitogenicity tests revealed no evidence of an increased mitogenic potential compared to human insulin.