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

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 (AUC(0-1440 min2:) 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 4-6h. 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: GIR(max) 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 t(max) (446 +/- 162 vs. 359 +/- 175 min) and lower AUC(0-240 min) (0.5 +/- 0.3 vs. 0.8 +/- 0.4g/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 (AUC(0-720 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 (AUC(0-1440 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.