Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304.

Abstract

AIMS:

To compare the pharmacokinetic and pharmacodynamic properties of subcutaneously injected NN304, a novel long-acting insulin analogue, to NPH-insulin during euglycaemic glucose clamps in 11 healthy volunteers.

METHODS:

On three study days NN304 was injected in three different doses (0.15, 0.3, 0.6 U/kg body weight), while NPH-insulin (0.3 U/kg) was injected in identical dose on two other days.

RESULTS:

Injection of NN304 resulted in a linear and proportional increase in total NN304 concentrations (AUC0-1440 min: 0.15 U/kg: 344+/-43, 0.3 U/kg: 666+/-82, 0.6 U/kg: 1295+/-210 nmol/l; P<0.001). Maximal concentrations (609+/-140, 1046+/-283, 2033+/-460 pmol/l; P<0.001) were reached after 4-6 h. The metabolic response (expressed as maximal glucose infusion rates (GIR)) induced by subcutaneous injection of NN304 did not show the pronounced peak seen with NPH-insulin in an identical dose: GIRmax 3.2+/-1.1 vs. 4.4+/-1.8 mg/kg/min (P<0.05 for 0.3 U/kg NN304 vs. NPH-insulin; mean of both study days with NPH-insulin, all others not significant). NN304 also showed a slower onset of action, as indicated by a significantly higher tmax (446+/-162 vs. 359+/-175 min) and lower AUC0-240min (0.5+/-0.3 vs. 0.8+/-0.4 g/kg/240min; P<0.05, respectively). The three different doses of NN304 induced a significantly different glucose consumption in the first 720 min after injection (AUC0-720 min 1.1+/-0.6, 1.9+/-0.8, 1.7+/-0.8 g/kg; P<0.05 for 0.15 U/kg), but not over the whole study period (AUC0-1440 min 1.8+/-1.1, 3.1+/-1.3, 2.8+/-1.4 g/kg).

CONCLUSIONS:

Injection of NN304 at different doses resulted in an increase in total NN304 concentration in a linear dose-response effect and a more even metabolic effect than NPH-insulin. However, we found no clear dose-response in its metabolic effect.

• Authors: L Heinemann, K Sinha, C Weyer, M Loftager, S Hirschberger, T Heise
• Journal: Diabetic medicine : a journal of the British Diabetic Association (Diabet Med) Vol. 16 Issue 4 Pg. 332-8 (Apr 1999) ISSN: 0742-3071 [Print] England
• PMID: 10220208 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Delayed-Action Preparations
• Hypoglycemic Agents
• Insulin
• Insulin, Long-Acting
• Insulin Detemir

Topics

• Acylation
• Adult
• Carrier Proteins (pharmacokinetics, therapeutic use)
• Delayed-Action Preparations
• Dose-Response Relationship, Drug
• Glucose Clamp Technique
• Humans
• Hypoglycemic Agents (pharmacokinetics, therapeutic use)
• Injections, Subcutaneous
• Insulin (analogs & derivatives, pharmacokinetics, therapeutic use)
• Insulin Detemir
• Insulin, Long-Acting
• Linear Models
• Male
• Reference Values
• Solubility