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.

Key words

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

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

References

• 1 Anderson J H, Brunelle R L, Koivisto V A, Trautmann M E, Vignati L, DiMarchi R. Improved mealtime treatment of diabetes mellitus using an insulin analogue.  Clin Therapeutics. 1997;  19 62-72
• 2 Becker R, Frick A, Wessels D, Scholtz H. Evaluation of the pharmacodynamic and pharmacokinetic profiles of insulin glulisine - a novel, rapid-acting, human insulin analogue.  Diabetologia. 2003;  46 Abs 775
• 4 Brange J, Owens D R, Kang S, Volund A. Monomeric insulins and their experimental and clinical implications.  Diabetes Care. 1990;  13 923-954
• 5 Brange J, Ribel U, Hansen J F, Dodson G, Hansen M T, Havelund S, Melberg S G, Norris F, Norris K, Snel L. Monomeric insulins obtained by protein engineering and their medical implications.  Nature. 1988;  333 679-682
• 6 Brems D N, Alter L A, Beckage M J, Chance R E, DiMarchi R D, Green L K, Long H B, Pekar A H, Shields J E, Frank B H. Altering the association properties of insulin by amino acid replacement.  Protein Eng. 1992;  5 527-533
• 7 DCCT . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.  N Engl J Med. 1993;  329 977-986
• 8 DiMarchi R D, Chance R E, Long H B, Shields J E, Slieker L J. Preparation of an insulin with improved pharmacokinetics relative to human insulin through consideration of structural homology with insulin-like growth factor I.  Horm Res. 1994;  41 (Suppl 2) 93-96
• 9 Eckert B, Agardh C D. Hypoglycaemia leads to an increased QT interval in normal men.  Clinical Physiology. 1998;  18 750-775
• 10 Frick A, Becker R, Wessels D, Scholtz H. Pharmacokinetic and glucodynamic profiles of insulin glulisine: an evaluation following subcutaneous administration at various injection sites.  Diabetologia. 2003;  46 Abs 776
• 11 Gillies P, Figgizz D, Lamb H. Insulin glargine.  Drugs. 2000;  59 253-260
• 12 Harris D A, Robinson R TCE, Ireland R H, Heller S R. Comparative effects of human soluble insulin and the new insulin analogue, insulin aspart, upon ventricular repolarization.  Diabetes. 1999;  48 (Suppl 1) A114-(Abstract 490)
• 13 Heinemann L, Woodworth J. Pharmacokinetics and glucodynamics of insulin lispro.  Drugs of Today. 1998;  34 (Suppl C) 23-36
• 14 Hennige A M, Kellerer M, Strack V, Metzinger E, Seipke G, Haring H U. New human insulin analogs: characteristics of insulin signalling in comparison to ASP(B10) and regular insulin.  Diabetologia. 1999;  42 A178
• 15 Kang S, Brange J, Burch A, Volund A, Owens D R. Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.  Diabetes Care. 1991;  14 942-948
• 16 Marques J LB, George E, Peacey S R, Harris N D, Macdonald, Cochrane T, Heller S R. Altered ventricular repolarization during hypoglycaemia in patients with diabetes.  Diabet Med. 1997;  14 648-654
• 17 Owens D R, Zinman B, Bolli G B. Insulins today and beyond.  Lancet. 2001;  358 739-746
• 18 Plum A, Agerso H, Andersen L. Pharmacokinetics of the rapid-acting insulin analog, insulin aspart, in rats, dogs, and pigs, and pharmacodynamics of insulin aspart in pigs.  Drug Metab Dispos. 2000;  28 155-160
• 3 Rave K, Bott S, Heinemann L, Sha S, Becker R HA, Willavize S A, Lee J, Heise T. Time-action profile of inhaled insulin (exubera) in comparison with subcutaneously-injected insulin lispro and regular human insulin.  Diabetes Care. 2005;  28 1077-1082
• 19 Renner R, Pfützner A, Trautmann M, Harzer O, Sauter K, Landgraf R. Use of insulin lispro in continuous subcutaneous insulin infusion treatment.  Diabetes Care. 1999;  22 784-788
• 20 Scholtz H E, Pretorius S G, Wessels D, Venter C, Potgieter M, Becker R. Equipotency of insulin glargine and regular human insulin on glucose disposal in healthy subjects following intravenous infusion.  Acta Diabetol. 2003;  40 156-16A
• 21 Schuirmann D J. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability.  J Pharmacokinet Biopharm. 1987;  15 657-680
• 22 Simpson K, Spencer C. Insulin aspart.  Drugs. 1999;  57 759-765
• 23 UKPDS . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.  Lancet. 1998;  352 837-853
• 24 Volund A, Brange J, Drejer K, Jensen I, Markussen J, Ribel U, Sorensen A R, Schlichtkrull J. In vitro and in vivo potency of insulin analogues designed for clinical use.  Diabet Med. 1991;  8 839-847
• 25 Vourinnen J, Tuominen J A. Fieller's confidence intervals for the ratio of two means in the assessment of average bioequivalence from cross-over data.  Stat Med. 1994;  13 2531-2545
• 26 Wilde M I, McTavish D. Insulin lispro: a review of its pharmacological properties and therapeutic use in the management of diabetes mellitus.  Drugs. 1997;  54 597-614

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