A Comparison of the Steady-State Pharmacokinetics and Pharmacodynamics of a Novel Rapid-Acting Insulin Analog, Insulin Glulisine, and Regular Human Insulin in Healthy Volunteers Using the Euglycemic Clamp Technique[1]

Abstract

Insulin glulisine is a new rapid-acting insulin analog. The aim of this study was to assess the glucodynamic efficacy of insulin glulisine compared with regular human insulin (RHI) using a manual euglycemic clamp technique. Steady-state pharmacokinetics of insulin glulisine, and its cardiac safety (ECG) and tolerability after intravenous administration, were also determined. This was a single center, randomized, open-label, two-way crossover study in healthy male subjects (n = 16). At the treatment visits subjects received an intravenous infusion of the study drug at a rate of 0.8 mU kg^-1 · min^-1 for 2 hours. Individual baseline glucose concentrations were targeted for euglycaemia and maintained with a manual adjusted 20 % glucose solution over the clamp period of a maximum 6 hours. A glulisine-specific antibody was used to quantify glulisine concentrations by radioimmunoassay, while a non-specific insulin antibody and C-peptide based correction for endogenous insulin was used to estimate exogenous human insulin (RHI). At steady state (90 - 120 min), insulin glulisine and RHI had equivalent glucose utilization (GIR-AUC_SS, 214 mg · kg^-1 for glulisine, 209 mg · kg^-1 for RHI) and infusion rates (GIR_SS, 1050 and 995 mg · min^-1 · kg^-1). Both insulins also presented equal total glucose disposal (GIR-AUC_{0 - clamp end}, 1050 and 995 mg · kg^-1) and onset of activity within 20 min. Insulin glulisine and RHI showed parallel time concentration profiles with similar distribution and elimination, but the different antibodies employed for radioimmunoassay impeded a quantitative comparison. There were no noteworthy individual or within-group changes in cardiac repolarisation parameters measured by 12-lead ECG during insulin glulisine infusion. In conclusion, insulin glulisine and RHI show similar distribution and elimination profiles and equivalent glucodynamic efficacy on a molar, unit-per-unit basis.

Insulin glulisine - regular human insulin - rapid-acting insulin analog - molar efficacy

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1 This study was performed at FARMOVS-PAREXEL (Pty) Ltd., Bloemfontein, Republic of South Africa. This study was sponsored by Aventis Pharmaceuticals.