Pharmacodynamic and pharmacokinetic properties of a premixed 85/15 human insulin preparation

Abstract

Background: Many patients with diabetes use mixtures of fast-acting (regular human) insulin and intermediate-acting (neutral protamine Hagedorn [NPH]) insulin to control their blood glucose levels. Premixed insulin is available in a 70%/30% mixture and a 50%/50% mixture of NPH/regular human insulin. For some patients, however, a premixed formulation containing ≥30% regular human insulin can provide too much fast-acting insulin, potentially causing an increased risk for hypoglycemia in the early hours after injection. Objective: The pharmacokinetic and pharmacodynamic properties of a premixed formulation of 85% NPH insulin and 15% regular human insulin (85/15) were compared with those of a premixed 70%/30% NPH/regular human insulin preparation and 100% NPH insulin. Methods: A 12-hour euglycemic clamp approach was used to assess glucose-lowering effects and serum insulin levels in 36 healthy male volunteers in a single-dose (0.5 U/kg), randomized, double-blind, 3-period, crossover study. Results: From 0 to 8 hours after injection, the glucose-lowering effects and serum insulin levels for the 85/15 premixed insulin preparation were significantly greater than those for NPH insulin ( P ≤ 0.05) but significantly less than those for the 70/30 premixed insulin preparation. The mean (± SEM) maximum glucose infusion rate (GIR max) was 8 ± 0.6 mg/(min·kg) for the 85/15 preparation, 7 ± 0.6 mg/(min·kg) for NPH, and 9 ± 0.6 mg/(min·kg) for the 70/30 preparation, with time to peak GIR (t max(GIR)) occurring at 313, 360, and 272 minutes, respectively. Time to peak insulin levels did not differ significantly for the 3 preparations, but maximum serum insulin concentration (C max(ins)) was significantly different between the groups (70/30 premix: 54 ± 2.2 μU/mL; 85/15 premix: 44 ± 2.4 μU/mL; NPH: 35 ± 1.7 μU/mL). Glucodynamic effect and serum insulin levels did not differ significantly among preparations during the interval from 8 to 12 hours after injection. Mean serum C-peptide levels ranged from ∼0.6 to 1.0 ng/mL for each preparation during the 12-hour period after injection. Conclusions: The 85/15 premixed insulin preparation demonstrated clinical pharmacokinetic and pharmacodynamic properties that were intermediate between, and significantly different from, those of NPH insulin and the 70/30 premixed insulin preparation.