NovoRapid FlexPen Mechanism of Action

Pharmacotherapeutic Group: Insulins and analogues for injection, fast-acting. ATC Code: A10AB05.
Pharmacology: Pharmacodynamics: Mechanism of Action: NovoRapid produces a more rapid onset of action compared to soluble human insulin, together with a lower glucose concentration, as assessed within the first 4 hrs after a meal. It has a shorter duration of action compared to soluble human insulin after SC injection.
When NovoRapid is injected SC, the onset of action will occur within 10-20 min of injection. The maximum effect is exerted between 1 and 3 hrs after injection. The duration of action is 3-5 hrs.
Adults: Clinical trials in patients with type 1 diabetes have demonstrated a lower postprandial blood glucose with NovoRapid compared to soluble human insulin. In 2 long-term, open-label trials in patients with type 1 diabetes comprising 1,070 patients and 884 patients, respectively, NovoRapid reduced glycosylated hemoglobin by 0.12 percentage points and by 0.15 percentage points compared to soluble human insulin, a difference of doubtful clinical significance.
Elderly: In a pharmacokinetic/pharmacodynamic (PK/PD) trial the relative differences in the PD properties between insulin aspart and soluble human insulin in the elderly patients with type 2 diabetes were similar to those seen in healthy subjects and younger patients with diabetes.
Children and Adolescents: When given to children, NovoRapid showed similar long-term glucose control compared to soluble human insulin.
In clinical trials for children and adolescents 2-17 years, the pharmacodynamic profile of insulin aspart in children was similar to that seen in adults.
Clinical trials in patients with type 1 diabetes have demonstrated a reduced risk of nocturnal hypoglycemia with insulin aspart compared to soluble human insulin. The risk of daytime hypoglycemia was not significantly increased.
Pregnancy: A clinical trial comparing safety and efficacy of insulin aspart versus soluble human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the fetus/newborn.
In addition, the data from a clinical trial including 27 women with gestational diabetes randomized to treatment with insulin aspart versus soluble human insulin showed similar safety profiles between treatments as well as a significant improvement in postprandial glucose control in the insulin aspart-treated group.
Pharmacokinetics: In NovoRapid, substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers as observed with soluble human insulin. NovoRapid is therefore more rapidly absorbed from the SC layer compared to soluble human insulin.
The time to maximum concentration is, on average, half of that for soluble human insulin. A mean maximum plasma concentration of 492 pmol/L was reached 40 min after an SC dose of 0.15 U/kg in type 1 diabetic patients. The insulin concentrations returned to baseline about 4-6 hrs after dose. The absorption rate was somewhat slower in type 2 diabetic patients, resulting in a lower C_max (352±240 pmol/L) and later t_max (60 min). The intra-individual variability in time to maximum concentration is significantly less for NovoRapid than for soluble human insulin, whereas the intra-individual variability in C_max for NovoRapid is larger.
Children and Adolescents: The pharmacokinetic and pharmacodynamic properties of NovoRapid were investigated in children and adolescents with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups with similar t_max as in adults. However, C_max differed between the age groups, stressing the importance of the individual titration of NovoRapid.
Elderly: The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly patients with type 2 diabetes were similar to those observed in healthy subjects and in younger patients with diabetes. A decreased absorption rate was observed in elderly subjects, resulting in a later t_max (82 min), whereas C_max was similar to that observed in younger subjects with type 2 diabetes and slightly lower than in subjects with type 1 diabetes.
Hepatic Impairment: In subjects with hepatic impairment, t_max was delayed to about 85 min (50 min in subjects with normal hepatic function) while AUC, C_max and CL/F were similar.
Renal Impairment: A single dose pharmacokinetic study of insulin aspart in 18 subjects with normal to severely impaired renal function was performed. No apparent effect of creatinine clearance values on AUC, C_max, CL/F and t_max of insulin aspart was found. Data were limited in subjects with moderate and severe renal impairment.
Subjects with renal failure necessitating dialysis treatment were not investigated.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and toxicity to reproduction.
In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.