Pharmacotherapeutic Group: Antidiabetic agent. Insulin and analogues, long-acting for injection. ATC Code: A10AE05.
Pharmacodynamics: Insulin detemir is a soluble, long-acting basal insulin analogue with a flat action profile with a prolonged duration of effect.
The time action profile of insulin detemir is significantly less variable than for NPH insulin and insulin glargine in Type 1 diabetes subjects. (See Table 1.)
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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. 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 duration of action is up to 24 hrs depending on dose providing an opportunity for once or twice-daily administration. If administered twice daily, steady state will occur after 2-3 dose administrations. For doses in the interval of 0.2-0.4 u/kg, Levemir exerts >50% of its maximum effect from 3-4 hrs and up to approximately 14 hrs after dose administration. Dose proportionality in pharmacodynamic response (maximum effect, duration of action, total effect) is observed after SC administration.
Lower day-to-day variability in FPG was demonstrated during treatment with Levemir compared to NPH in long-term clinical trials.
Studies in patient with type 2 diabetes treat with basal insulin combination with oral antidiabetic drugs demonstrated that glycaemic control (HBA10
) with Levemir is comparable to NPH insulin and insulin glargine and associated with less weight gain, see Table 2. In the study versus insulin glargine, insulin detemir was allowed to be administered once or twice daily whereas insulin glargine was to be administered once a day, 55% of the insulin detemir-treated subjects completed the 52 weeks of treatment on the twice daily regimen. (See Table 2.)
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In trials with the use of OAD-insulin combination therapy Levemir treatment resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH insulin.
In long-term treatment trials in patients with type 1 diabetes, fasting plasma glucose was improved with Levemir compared with NPH insulin when given as basal/bolus therapy including in children and adolescents aged 6-17. Glycaemic control (HbA1c) with Levemir is comparable to NPH insulin, with a lower risk of norturnal hypoglycaemia and no associated weight gain.
Antibody development has been observed with the use of Levemir. However, this does not appear to have any impact on glycaemic control.
Absorption: Maximum serum concentration is reached between 6 and 8 hrs after administration. When administered twice daily, steady state serum concentrations are reached after 2-3 dose administrations.
Intra-subject variation in absorption is lower for Levemir than for other basal insulin preparations.
There are no clinically relevant differences between genders in pharmacokinetic properties of insulin detemir. The absolute bioavailability of insulin detemir when administered SC 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.
Metabolism: Degradation of insulin detemir is similar to that of human insulin; all metabolites formed are inactive. 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 drugs.
Elimination: The terminal t½
after SC administration is determined by the rate of absorption from the subcutaneous tissue. The terminal t½
is between 5 and 7 hrs depending on dose.
Linearity: Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after SC administration in the therapeutic dose range.
Special Populations: The pharmacokinetic properties of insulin detemir were investigated in children (6-12 years) and adolescents (13-17 years) and compared to adults with type 1 diabetes. There was no clinically relevant difference in pharmacokinetic properties.
There was no clinically relevant difference in pharmacokinetics of insulin detemir between elderly and young subjects or between subjects with renal or hepatic impairment and healthy subjects. No clinically relevant differences in the pharmacokinetics of insulin detemir are expected between healthy subjects and subjects with renal or hepatic impairment, based on the studies performed. 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.
Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction. Receptor affinity data and in vitro
mitogenicity tests revealed no evidence of an increased mitogenic potential compared to human insulin.