Insulin degludec binds specifically to the human insulin receptor and results in the same pharmacological effects as human insulin.
The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
Insulin degludec is a basal insulin that upon subcutaneous injection is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect (see figure 1). During a period of 24 hours with once-daily treatment, the glucose-lowering effect of insulin degludec, in contrast to insulin glargine, was evenly distributed between the first and second 12 hours (AUCGIR,0-12h,SS/AUCGIR,total,SS = 0.5).
Figure 1. Glucose infusion rate profile, smoothed, steady state – Mean profile 0-24 hours – IDeg 100 units/mL 0.6 units/kg – Trial 1987:
The duration of action of insulin degludec is beyond 42 hours within the therapeutic dose range.
Steady state will occur after 2–3 days of dose administration.
The day-to-day variability, expressed as the coefficient of variation, in glucose-lowering effect during one dosing interval of 0-24 hours at steady state (AUCGIR,τ,SS) is 20% for insulin degludec, which is significantly lower than for insulin glargine (100 units/mL).
The total glucose-lowering effect of insulin degludec increases linearly with increasing doses.
The total glucose-lowering effect is comparable for insulin degludec 100 units/mL and 200 units/mL after administration of the same doses of the two products.
There is no clinically relevant difference in the pharmacodynamics of this medicinal product between elderly and younger adult patients.
After subcutaneous injection, soluble and stable multi-hexamers are formed creating a depot of insulin in the subcutaneous tissue. Insulin degludec monomers gradually separate from the multi-hexamers thus resulting in a slow and continuous delivery of insulin degludec into the circulation.
Steady-state serum concentration is reached after 2–3 days of daily insulin degludec administration.
During a period of 24 hours with once-daily treatment, the exposure of insulin degludec was evenly distributed between the first and second 12 hours. The ratio between AUCGIR,0-12h,SS and AUCGIR,τ,SS was 0.5.
The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma.
Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive.
The half-life after subcutaneous administration of insulin degludec is determined by the rate of absorption from the subcutaneous tissue. The half-life of insulin degludec is approximately 25 hours independent of dose.
Dose proportionality in total exposure is observed after subcutaneous administration within the therapeutic dose range. In direct comparison, requirements for bioequivalence are met for insulin degludec 100 units/mL and insulin degludec 200 units/mL (based on AUCIDeg,τ,SS and Cmax,IDeg,SS).
There is no gender difference in the pharmacokinetic properties of this medicinal product.
There is no difference in the pharmacokinetics of insulin degludec between elderly and younger adult patients, between races or between healthy subjects and patients with renal or hepatic impairment.
Pharmacokinetic properties of insulin degludec in children (1-11 years) and adolescents (12-18 years) were at steady state comparable to those observed in adults with type 1 diabetes mellitus. Total exposure after a single dose was, however, higher in children and adolescents than in adults with type 1 diabetes mellitus.
Non-clinical data reveal no safety concerns for humans based on studies of safety pharmacology, repeated dose toxicity, carcinogenic potential, and toxicity to reproduction.
The ratio of mitogenic relative to metabolic potency for insulin degludec is comparable to that of human insulin.
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