Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, fast-acting, ATC code: A10AB04

The primary activity of insulin lispro is the regulation of glucose metabolism.

In addition, insulins have several anabolic and anti-catabolic actions on a variety of different tissues.
Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and protein synthesis and amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output.

Insulin lispro has a rapid onset of action (approximately 15 minutes), thus allowing it to be given closer to a meal (within zero to 15 minutes of the meal) when compared to soluble insulin (30 to 45 minutes before). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to soluble insulin.

Clinical trials in patients with type 1 and type 2 diabetes have demonstrated reduced postprandial hyperglycaemia with insulin lispro compared to soluble human insulin.
The time course of insulin lispro action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature and physical activity.
The typical activity profile following subcutaneous injection is illustrated below.

Figure 1:



The above representation (figure 1) reflects the relative amount of glucose over time required to maintain the subject's whole blood glucose concentrations near fasting levels and is an indicator of the effect of these insulins (100 units/ml) on glucose metabolism over time.

The pharmacodynamic responses of insulin lispro 200 units/ml solution for injection were similar to those for insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects as shown in the graph below (figure 2).



800

700
Insulin lispro 200 units/ml
Glucose    600                             Insulin lispro 100 units/ml Infusion
500
Rate
(mg/min)   400

300

200
100

0

0     1       2       3        4        5         6      7      8
Time (hr)



Figure 2: Arithmetic mean glucose infusion rate versus time profiles following subcutaneous administration of 20 units of insulin lispro 200 units/ml or insulin lispro 100 units/ml 
In patients with type 2 diabetes on maximum doses of sulphonyl urea agents, studies have shown that the addition of insulin lispro significantly reduces HbA1c compared to sulphonyl urea alone. The reduction of HbA1c would also be expected with other insulin products e.g. soluble or isophane insulins.

Clinical trials in patients with type 1 and type 2 diabetes have demonstrated a reduced number of episodes of nocturnal hypoglycaemia with insulin lispro compared to soluble human insulin. In some studies, reduction of nocturnal hypoglycaemia was associated with increased episodes of daytime hypoglycaemia.

The glucodynamic response to insulin lispro is not affected by renal or hepatic function impairment.
Glucodynamic differences between insulin lispro and soluble human insulin, as measured during a glucose clamp procedure, were maintained over a wide range of renal function.

Insulin lispro has been shown to be equipotent to human insulin on a molar basis but its effect is more rapid and of a shorter duration.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical relevance of these kinetics, it is more appropriate to examine the glucose utilisation curves (as discussed in 5.1).

Insulin lispro maintains more rapid absorption when compared to soluble human insulin in patients with renal impairment. In patients with type 2 diabetes over a wide range of renal function the pharmacokinetic differences between insulin lispro and soluble human insulin were generally maintained and shown to be independent of renal function. Insulin lispro maintains more rapid absorption and elimination when compared to soluble human insulin in patients with hepatic impairment.

Insulin lispro 200 units/ml solution for injection was bioequivalent to insulin lispro 100 units/ml solution for injection after subcutaneous administration of a single 20 unit dose in healthy subjects. Time to maximum concentration was also similar between formulations.