Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304.
OBJECTIVE
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.
Heinemann
L
L
Department of Metabolic Diseases and Nutrition, WHO Collaborating Centre for Diabetes, Heinrich-Heine-University Düsseldorf, Germany.
Sinha
K
K
Weyer
C
C
Loftager
M
M
Hirschberger
S
S
Heise
T
T
D000215:Acylation; D000328:Adult; D002352:Carrier Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069057:Insulin Detemir; D049528:Insulin, Long-Acting; D016014:Linear Models; D008297:Male; D012016:Reference Values; D012995:Solubility
D002352:Carrier Proteins; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069057:Insulin Detemir