NovoMix 30 FlexPen Mechanism of Action

Pharmacotherapeutic Group: Drugs used in diabetes. Insulins and analogs for injection, intermediate-acting combined with fast-acting. ATC Code: A10AD05.
Pharmacology: Pharmacodynamics: NovoMix 30 is a biphasic suspension of insulin aspart (rapid-acting human insulin analog) and protamine-crystallized insulin aspart (intermediate-acting human insulin analog). The suspension contains rapid-acting and intermediate-acting insulin aspart in the ratio 30/70. Insulin aspart is equipotent to human insulin on a molar basis. HbA_1c after 16 weeks of treatment did not differ between patients with biphasic insulin aspart 30 combined with metformin and patients with metformin plus sulfonylurea. In this trial, 57% of the patients had baseline HbA_1c >9%. In these patients, treatment with biphasic insulin aspart 30 in combination with metformin resulted in significantly lower HbA_1c than metformin in combination with sulfonylurea.
In 1 study, patients with type 2 diabetes, insufficiently controlled on oral hypoglycemic agents alone, were randomized to treatment with twice daily biphasic insulin aspart 30 (117 patients) or once daily insulin glargine (116 patients). After 28 weeks treatment following the dosing guideline, the mean reduction in HbA_1c was 2.8% with biphasic insulin aspart 30 (mean at baseline=9.7%). With biphasic insulin aspart 30, 66% and 42% of the patients reached HbA_1c levels below 7% and 6.5%, respectively, and mean FPG was reduced by about 7 mmol/L (from 14.0 mmol/L at baseline to 7.1 mmol/L).
In patients with type 2 diabetes, a meta-analysis showed a reduced risk of overall nocturnal hypoglycemic episodes and major hypoglycemia with biphasic insulin aspart 30 compared to biphasic human insulin 30. The risk of overall daytime hypoglycemic episodes was higher in patients treated with biphasic insulin aspart 30.
Pediatric Population: A 16-week clinical trial comparing postprandial glycemic control of meal-related biphasic insulin aspart 30 with meal-related human insulin/biphasic human insulin 30 and bedtime neutral protamine hagedorn (NPH) insulin was performed in 167 subjects 10-18 years. Mean HbA_1c remained similar to baseline throughout the trial in both treatment groups, and there was no difference in hypoglycemia rate with biphasic insulin aspart 30 or biphasic human insulin 30.
In a smaller (54 subjects) and younger (age range 6-12 years) population, treated in a double-blind, cross-over trial (12 weeks on each treatment) the rate of hypoglycemic episodes and the postprandial glucose increase was significantly lower with biphasic insulin aspart 30 compared to biphasic human insulin 30.
Final HbA_1c was significantly lower in the biphasic human insulin 30 treated group compared with biphasic insulin aspart 30.
Elderly: The pharmacodynamic properties of biphasic insulin aspart 30 have not been investigated in the elderly. However, a randomized, double-blind cross-over pharmacokinetics/pharmacodynamics (PK/PD) trial comparing insulin aspart with soluble human insulin was performed in elderly patients with type 2 diabetes (19 patients 65-83 years, mean age 70 years). The relative differences in the pharmacodynamic properties (GIR_max, AUC_{GIR, 0-120 min}) between insulin aspart and soluble human insulin in the elderly were similar to those seen in healthy subjects and in younger subjects with diabetes.
Pharmacokinetics: In insulin aspart substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers as observed with human insulin. The insulin aspart in the soluble phase of biphasic insulin aspart 30 comprises 30% of the total insulin; this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 70% is in crystalline form as protamine-crystallized insulin aspart; this has a prolonged absorption profile similar to human NPH insulin. The maximum serum insulin concentration is, on average, 50% higher with biphasic insulin aspart 30 than with biphasic human insulin 30. The time to maximum concentration is, on average, half of that for biphasic human insulin 30. In healthy volunteers, a mean maximum serum concentration of 140±32 pmol/L was reached about 60 min after an SC dose of 0.2 U/kg body weight. The mean t_½ of biphasic insulin aspart 30, reflecting the absorption rate of the protamine bound fraction, was about 8-9 hrs. Serum insulin levels returned to baseline 15-18 hrs after a SC dose. In type 2 diabetic patients, the maximum concentration was reached about 95 min after dosing and concentrations well above zero for not less than 14 hrs post-dosing were measured.
Renal and Hepatic Impairment: The pharmacokinetics of biphasic insulin aspart 30 has not been investigated in patients with renal or hepatic impairment.
Pediatric Population: The pharmacokinetics of biphasic insulin aspart 30 has not been investigated in children or adolescents.
However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children (6-12 years) and adolescents (13-17 years) 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 insulin aspart.
Elderly: The pharmacokinetic properties of biphasic insulin aspart 30 have not been investigated in the elderly patients. However, the relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly subjects (65-83 years, mean age 70 years) with type 2 diabetes, were similar to those observed in healthy subjects and in younger subjects with diabetes. A decreased absorption rate was observed in elderly subjects, resulting in a later t_max [82 (interquartile range: 60-120) 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.
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.