Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glulisine

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Insulin glulisine injection [3B-Lys, 29B-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin.

The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption.

Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg.

The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075–0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general.

The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly — but consistently —greater than those of insulin lispro in healthy volunteers across a wide range of BMIs.

Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro.

Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and adds to the flexibility in postprandial blood glucose control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Table I
Fig. 3
Table II
Table III
Table IV
Table V
Fig. 4

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Home PD, Alberti KGMM. Insulin therapy. Chichester: John Wiley & Sons, 1992

    Google Scholar 

  2. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977–86

    Article  Google Scholar 

  3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131): 837–53

    Article  Google Scholar 

  4. Hirsch IB. Intensive treatment of type 1 diabetes. Med Clin North Am 1998; 82: 689–719

    Article  PubMed  CAS  Google Scholar 

  5. Rosenstock J. Insulin strategies in type 2 diabetes. In: Goldfine ID, Rushakoff RJ, editors. Diabetes and carbohydrate metabolism. Endotext.com [online]. Available from URL: http://www.mdtext.com/diabetes/index.htm [Accessed 2007 Oct 30]

  6. Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2001; 358: 739–46

    Article  PubMed  CAS  Google Scholar 

  7. Bolli GB. Insulin treatment in type 1 diabetes. Endocr Pract 2006; 12 Suppl. 1:105–9

    PubMed  Google Scholar 

  8. Heise T, Heinemann L. Rapid and long-acting analogues as an approach to improve insulin therapy: an evidence-based medicine assessment. Curr Pharm Des 2001; 7(14): 1303–25

    Article  PubMed  CAS  Google Scholar 

  9. Brems DN, Alter LA, Beckage MJ, et al. Altering the association properties of insulin by amino acid replacement. Protein Eng 1992; 5(6): 527–33

    Article  PubMed  CAS  Google Scholar 

  10. Heinemann L, Heise T, Jorgensen LN, et al. Action profile of the rapid acting insulin analogue: human insulin B28Asp. Diabet Med 1993; 10(6): 535–9

    Article  PubMed  CAS  Google Scholar 

  11. Howey DC, Bowsher RR, Brunelle RL, et al. [Lys(B28), Pro(B29)]-human insulin: a rapidly absorbed analogue of human insulin. Diabetes 1994; 43(3): 396–402

    Article  PubMed  CAS  Google Scholar 

  12. Sluzky V, Tamada JA, Klibanov AM, et al. Kinetics of insulin aggregation in aqueous solutions upon agitation in the presence of hydrophobic surfaces. Proc Natl Acad Sci U S A 1991; 88(21): 9377–81

    Article  PubMed  CAS  Google Scholar 

  13. Rahuel-Clermont S, French CA, Kaarsholm NC, et al. Mechanisms of stabilization of the insulin hexamer through allosteric ligand interactions. Biochemistry 1997; 36(19): 5837–45

    Article  PubMed  CAS  Google Scholar 

  14. Eli Lilly and Company. Humalog® insulin lispro injection (rDNA origin) [online]. Available from URL: http://www.fda.gov/cder/foi/label/2004/20563se3-024_humalog_lbl.pdf [Accessed 2007 Oct 30]

  15. Becker RHA, Frick AD, Wessels D, et al. Evaluation of the pharmacodynamic and pharmacokinetic profiles of insulin glulisine: a novel, rapid-acting, human insulin analogue [abstract]. Diabetologia 2003; 46: A775

    Google Scholar 

  16. European Medicines Agency Committee for Medicinal Products for Human Use. Apidra European public assessment report: Annex I. Summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/hu-mandocs/PDFs/EPAR/apidra/H-557-PI-en.pdf [Accessed 2007 Dec 7]

  17. Aventis Pharmaceuticals Inc. Apidra™ insulin glulisine (rDNA origin) injection [online]. Available from URL: http://www.fda.gov/cder/foi/label/2004/021629lbl.pdf [Accessed 2007 Oct 30]

  18. Becker RH. Insulin glulisine complementing basal insulins: a review of structure and activity. Diabetes Technol Ther 2007; 9(1): 109–21

    Article  PubMed  CAS  Google Scholar 

  19. Ahmad A, Uversky VN, Hong D, et al. Early events in the fibrillation of monomeric insulin. J Biol Chem 2005; 280(52): 42669–75

    Article  PubMed  CAS  Google Scholar 

  20. Becker R, Wollmer A, Seipke G. Self-association of insulin glulisine in solution: results of a comparative circular dichroism study [abstract]. Diabetes 2007; 56 Suppl. 1: A124

    Google Scholar 

  21. European Medicines Agency Committee for Medicinal Products for Human Use. Apidra European public assessment report: scientific discussion [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/apidra/121804en6.pdf [Accessed 2007 Dec 7]

  22. Poulsen C, Langkjaer L, Worsoe C. Precipitation of insulin aspart and insulin glulisine products used for continuous subcutaneous insulin infusion. Diabetes Technol Ther 2007; 9(1): 26–35

    Article  PubMed  CAS  Google Scholar 

  23. Blundell T, Dodson G, Hodgkin D, et al. Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv Prot Chem 1972; 26: 279–402

    Article  CAS  Google Scholar 

  24. Poulsen C, Langkjaer L, Worsoe C. Precipitation of insulin products used for continuous subcutaneous insulin infusion. Diabetes Technol Ther 2005; 7(1): 142–50

    Article  PubMed  CAS  Google Scholar 

  25. DiMarchi RD, Chance RE, Long HB, et al. 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: 93–6

    Article  PubMed  CAS  Google Scholar 

  26. Binder C. Absorption of injected insulin: a clinical-pharmacological study. Acta Pharmacol Toxicol (Copenh) 1969; 27 Suppl. 2: 1–84

    Article  Google Scholar 

  27. Bakaysa DL, Radziuk J, Havel HA, et al. Physicochemical basis for the rapid time-action of LysB28ProB29-insulin: dissociation of a protein-ligand complex. Protein Sci 1996; 5(12): 2521–31

    Article  PubMed  CAS  Google Scholar 

  28. Data on file, sanofi-aventis, 2001

  29. Heinemann L, Anderson Jr JH. Measurement of insulin absorption and insulin action. Diabetes Technol Ther 2004; 6(5): 698–718

    Article  PubMed  CAS  Google Scholar 

  30. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237(3): E214-23

    Google Scholar 

  31. Becker RH, Frick AD, Burger F, et al. 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. Exp Clin Endocrinol Diabetes 2005; 113(5): 292–7

    Article  PubMed  CAS  Google Scholar 

  32. Data on file, sanofi-aventis, 2003

  33. Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev 1998; 19(5): 608–24

    Article  PubMed  CAS  Google Scholar 

  34. Frick AD, Becker RHA, Wessels D, et al. Pharmacokinetic and glucodynamic profiles of insulin glulisine: an evaluation following subcutaneous administration at various injection sites [abstract]. Diabetologia 2003; 46: A776

    Google Scholar 

  35. Data on file, sanofi-aventis, 2000

  36. Becker RH, Frick AD, Burger F, et al. Insulin glulisine, a new rapid-acting insulin analogue, displays a rapid time-action profile in obese non-diabetic subjects. Exp Clin Endocrinol Diabetes 2005; 113(8): 435–43

    Article  PubMed  CAS  Google Scholar 

  37. Burger F, Scholtz H, Frick AD, et al. Pharmacodynamics (PD) and pharmacokinetics (PK) of insulin glulisine (GLU) versus insulin lispro (IL) and regular human insulin (RHI) in patients with type 1 diabetes [abstract]. Diabetes 2004; 53 Suppl. 2: A557

    Google Scholar 

  38. Rave K, Klein O, Frick AD, et al. Advantage of prenieal-injected insulin glulisine compared with regular human insulin in subjects with type 1 diabetes. Diabetes Care 2006; 29(8): 1812–7

    Article  PubMed  CAS  Google Scholar 

  39. Becker R, Frick A, Heinemann L, et al. Dose response relation of insulin glulisine (GLU) in subjects with type 1 diabetes (TIDM) [abstract]. Diabetes 2005; 54 Suppl. 1: A332

    Google Scholar 

  40. Danne T, Deiss D, Hopfenmuller W, et al. Experience with insulin analogues in children. Horm Res 2002; 57 Suppl. 1: 46–53

    Article  PubMed  CAS  Google Scholar 

  41. Danne T, Becker RH, Heise T, et al. Pharmacokinetics, prandial glucose control, and safety of insulin glulisine in children and adolescents with type 1 diabetes. Diabetes Care 2005; 28(9): 2100–5

    Article  PubMed  CAS  Google Scholar 

  42. Becker RHA, Frick AD, Kapitza C, et al. Pharmacodynamics (PD) and pharmacokinetics (PK) of insulin glulisine compared with insulin lispro (IL) and regular human insulin (RHI) in patients with type 2 diabetes [abstract]. Diabetes 2004; 53 Suppl. 2: A119

    Google Scholar 

  43. Becker RH, Frick AD, Nosek L, et al. Dose-response relationship of insulin glulisine in subjects with type 1 diabetes. Diabetes Care 2007; 30(10): 2506–7

    Article  PubMed  CAS  Google Scholar 

  44. Data on file, sanofi-aventis, 2004

  45. US FDA Center for Drug Evaluation and Research. New and generic drug approvals: Apidra™ (application number 21–629). Clinical pharmacology and biopharmaceutics reviews [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2004/21-629_Apidra_BioPharmr.pdf [Accessed 2007 Nov 27]

  46. Overmann H, Heinemann L. Injection-meal interval: recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract 1999; 43(2): 137–42

    Article  PubMed  CAS  Google Scholar 

  47. ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care 1996; 19(12): 1437–40

    Article  PubMed  Google Scholar 

  48. Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care 1999; 22(9): 1501–6

    Article  PubMed  CAS  Google Scholar 

  49. Data on file, sanofi-aventis, 2002

  50. Frick A, Scholtz H, Burger F, et al. Absorption of insulin glulisine when mixed with NPH insulin [abstract]. Diabetes 2004; 53 Suppl. 2: A321

    Article  Google Scholar 

  51. Joseph SE, Korzon-Burakowska A, Woodworth JR, et al. The action profile of lispro is not blunted by mixing in the syringe with NPH insulin. Diabetes Care 1998; 21(12): 2098–102

    Article  PubMed  CAS  Google Scholar 

  52. Rave K, Nosek L, Heinemann L, et al. Insulin glulisine: pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with insulin lispro and regular human insulin in Japanese and Caucasian volunteers [abstract]. Diabetes 2004; 53 Suppl. 2: A143

    Google Scholar 

  53. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia 1984; 27(3): 351–7

    Article  PubMed  CAS  Google Scholar 

  54. Jaros M, Martinek V, Piechatzek R, et al. Pharmacokinetics of insulin glulisine in non-diabetic renally impaired patients [abstract]. Diabetes 2004; 53 Suppl. 2: A321

    Article  Google Scholar 

  55. Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23(2): 201–29

    Article  PubMed  CAS  Google Scholar 

  56. Heise T, Nosek L, Spitzer H, et al. Insulin glulisine: a faster onset of action compared with insulin lispro. Diabetes Obes Metab 2007; 9(5): 746–53

    Article  PubMed  CAS  Google Scholar 

  57. Data on file, sanofi-aventis, 2005

  58. Luzio SD, Peter P, Dunseath GJ, et al. Comparison of the pharmacodynamics and pharmacokinetics of bolus subcutaneous insulin glulisine and insulin lispro in obese patients with type 2 diabetes [abstract]. Diabetologia 2005; 48 Suppl. 1: A844

    Google Scholar 

  59. Renner R, Pfutzner A, Trautmann M, et al. Use of insulin lispro in continuous subcutaneous insulin infusion treatment: results of a multicenter trial. German Humalog-CSII Study Group. Diabetes Care 1999; 22(5): 784–8

    Article  PubMed  CAS  Google Scholar 

  60. Retnakaran R, Hochman J, DeVries JH, et al. Continuous subcutaneous insulin infusion versus multiple daily injections: the impact of baseline Alc. Diabetes Care 2004; 27(11): 2590–6

    Article  PubMed  CAS  Google Scholar 

  61. Hirsch IB, Bode BW, Garg S, et al. Continuous subcutaneous insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin glargine in type 1 diabetic patients previously treated with CSII. Diabetes Care 2005; 28(3): 533–8

    Article  PubMed  Google Scholar 

  62. Bode B, Weinstein R, Bell D, et al. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care 2002; 25(3): 439–44

    Article  PubMed  CAS  Google Scholar 

  63. Hoogma RP, Schumicki D. Safety of insulin glulisine when given by continuous subcutaneous infusion using an external pump in patients with type 1 diabetes. Horm Metab Res 2006; 38(6): 429–33

    Article  PubMed  CAS  Google Scholar 

  64. DeFelippis MR, Bell MA, Heyob JA, et al. In vitro stability of insulin lispro in continuous subcutaneous insulin infusion. Diabetes Technol Ther 2006; 8(3): 358–68

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was sponsored by sanofi-aventis. Editorial support was provided by the Global Publication Group of sanofi-aventis. Both authors are employees of sanofi-aventis.

Author information

Authors and Affiliations

  1. sanofi-aventis, Frankfurt/Main, Germany

    Reinhard H. A. Becker & Annke D. Frick

Authors
  1. Reinhard H. A. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annke D. Frick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reinhard H. A. Becker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Becker, R.H.A., Frick, A.D. Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glulisine. Clin Pharmacokinet 47, 7–20 (2008). https://doi.org/10.2165/00003088-200847010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200847010-00002

Keywords

Search

Navigation