To study the pharmacokinetics and pharmacodynamics of the 40/60 premixed recombinant human insulin injection preparation, and to compare with 30/70 preparation, regular insulin, and neutral protamine Hagedorn (NPH).

In this positive control, single dose, open label, Latin square crossover study, 20 male healthy volunteers were recruited from May 2006 to March 2007, and divided into four groups. On 4 test days, 40/60 preparation, 30/70 preparation, regular insulin, and NPH were administered to each of the 4 groups, the interval was 7-70 days before 2 test days. The pharmacokinetics and pharmacodynamics were evaluated by euglycemic glucose clamp technique.

According to the analysis of variance, there were statistically significant differences in pharmacokinetics and pharmacodynamics of the 4 insulin formulations between the 4 groups (all P<0.05). For the 40/60 premixed recombinant human insulin, the pharmacokinetic parameter time to peak (T_max) and mean retention time (MRT) were (105.00±24.33) minutes and (321.77±56.29) minutes, respectively; the glucose-lowering effects reflected by the pharmacodynamic parameter T_max and MRT were (167.75±26.48)minutes and (248.33±14.96)minutes, respectively. Compared with 30/70 premixed recombinant human insulin, 40/60 preparation showed no significant differences in the pharmacokinetics parameters of blood insulin concentration, including peak concentration [(91.67±13.03)mU/L vs. (84.96±14.75)mU/L, P=0.119], T_max [(105.00±24.33)minutes vs. (122.25±39.35)minutes, P=0.128], MRT [(321.77±56.29)minutes vs. (332.12±49.20)minutes, P=0.645] and area under the curve in 0-16 hours [AUC_{Ins 0-16}, (24 918±6 610)h·mU/L vs. (26 768±8 032)h·mU/L, P=0.084]; however, statistically significant differences were observed in AUC_{Ins 0-4} [(16 991±3 673)h·mU/L vs. (12 407±3 441)h·mU/L, P=0.042] and AUC_{Ins 0-8} [(23 283±4 939)h·mU/L vs. (19 397±5 314)h·mU/L, P=0.046]. Pharmacodynamic parameters showed no statistically significant differences (all P>0.05). Compared with 30/70 premixed insulin, the relative bioavailability of 40/60 premixed insulin was (118.9±35.9)%, and the relative biological effectiveness was (106.6±35.2)%. There was no clinically significant abnormalities in the safety indexes before and after the tests. No hypoglycemic events, allergic reactions, or local injection adverse reaction occurred in this trial.

The 40/60 premixed recombinant human insulin preparation demonstrated different properties in insulin absorption in 8 hours after injection compared with the 30/70 preparation, mainly because of the difference in proportions of short- and intermediate-acting insulin in the mixture. This new premixed insulin may provide a new option for personalized diabetes management.

Euglycemic glucose clamp; Insulin preparation; Pharmacokinetics; Pharmacodynamics; Bioequivalence