Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue NN304 in comparison to NPH insulin in humans

Abstract

NN304 is a long-acting insulin analogue that is acylated with a 14-C-fatty acid chain. Protraction of action of this novel insulin analogue is due not to slow absorption after subcutaneous administration but to reversible binding to albumin. We investigated the pharmacokinetic and pharmacodynamic properties of insulin analogue NN304 (0.3 and 0.6 U/kg) in comparison to NPH insulin (0.3 and 0.6 IU/kg) in 10 healthy volunteers performing a randomised, double-blind, cross-over, placebo-controlled glucose clamp study. During the observation period of 24 hours the areas under the insulin curve for NPH[0.3 IU/kg] vs. NPH[0.6 IU/kg] were 60 vs. 102 nmol min l(-1) (p<0.01) and for insulin analogue NN304[0.3 U/kg] vs. NN304[0.6 U/kg] 490 vs. 932 nmol min l(-1) (p <0.001), suggesting a clear dose-response relationship for both NPH insulin and NN304. The amount of disposed glucose (area under the curve of glucose infusion) differed with statistical significance between the five treatments and was highest with NPH[0.6 IU/kg] (2671 mg/kg) and lowest with placebo (265 mg/kg). However, area under the curve of glucose infusion after treatment with NN304 was only 36% (dose of 0.3 U/kg) and 24% (dose of 0.6 U/kg) of that observed with corresponding doses of NPH insulin. Moreover, increasing dosages of NN304 failed to demonstrate a significant dose-response with regard to the area under the curve of glucose infusion. This study demonstrates that the principle of protracted insulin action of NN304 by reversible binding to albumin is effective in humans albeit at a much lower rate of glucose utilisation when compared to NPH insulin. Thus, in contrast to animal studies NN304 and NPH insulin can not be considered equipotent in humans.

A Double-Blind, Randomized, Dose-Response Study Investigating the Pharmacodynamic and Pharmacokinetic Properties of the Long-Acting Insulin Analog Detemir

“…These insulin analogs make use of different principles for achieving a protracted insulin profile, such as changing the isoelectric point (insulin glargine) or acylation of the insulin molecule (insulin detemir). Previous studies have confirmed both a delayed and a sustained blood glucoselowering effect with insulin detemir compared with NPH insulin in healthy subjects (10,11). However, the results show that a higher molar dose of insulin detemir is needed to achieve comparable glycemic control similar to that observed with NPH insulin (10).…”

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes

“…Thus an insulin analogue bound to one or more plasma proteins has greater access to hepatocytes than to peripheral target tissues. Insulin detemir (NN304) (B29Lys(ε-tetradecanoyl),desB30 human insulin) is a soluble insulin analogue with a C 14 fatty acid side-chain at position B29 [4]. In the monomeric state, this side-chain binds to the fatty acid binding sites of albumin in plasma, developing equilibrium between free and albumin bound analogue [5].…”

Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir

“…In fact, in vivo pharmacodynamic (and clinical) studies have shown that insulin detemir does have a reduced molar potencyFabout 25% that of human insulin. 44,45 This is probably due to a relatively reduced rate of access from the plasma compartment to the interstitial fluid with an increased rate of nonreceptor-mediated clearance. 46 Consequently, insulin detemir is marketed in a formulation that is four times the molar strength of human insulin so as to maintain parity in unit doses and injection volumes.…”