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Introducing insulin detemir

Introducing insulin detemir. Peter Kurtzhals Denmark. Agenda. Development of a long-acting insulin analogue Insulin detemir ( Levemir ® ) Mechanism of protraction Safety. Major advances in insulin development. 1922. Isolation of insulin. Banting & Best. Scott et al. 1934.

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Introducing insulin detemir

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  1. Introducing insulin detemir Peter Kurtzhals Denmark

  2. Agenda • Development of a long-acting insulin analogue • Insulin detemir (Levemir®) • Mechanism of protraction • Safety

  3. Major advances in insulin development 1922 Isolation of insulin Banting & Best Scott et al. 1934 Zinc-insulin crystallization Hagedorn et al.Scott & Fisher 1936 Protamine insulin 1946 Isophane insulin, NPH Krayenbühl & Rosenberg 1952 Lente series Hallas-Mølleret al. Neutral regular insulin Schlichtkrullet al. 1961 Monocomponent insulin Schlichtkrullet al. 1972 Adapted from Brange, Diabetes Care 1990;13:923-954.

  4. Development of semi- and biosynthetic insulin 1977 Cloning of the rat insulin gene Ullrich et al. 1979 Porcine to human insulin Markussen et al. 1979 Human insulin in E. coli Goeddel et al. 1986 Human insulin in yeast Markussen, Thim et al. 1987 Rapid-acting insulin analogues Brange et al. 1987 Long-acting insulin analogues Markussen et al. Adapted from Brange, Diabetes Care 1990;13:923-954.

  5. Desirable properties of improved basal insulin Safety Efficacy Kinetics

  6. Sites for modification of insulin s s A-chain A21 A1 s s B-chain s s B1 B30 Light blue: residues preserved in naturally occurring insulins Red: residues involved in receptor binding Kaarsholm & Ludvigsen. Receptor 1995;5:1-8.

  7. s s A1 A21 s s Detemir K s s B1 B30 Lispro K P AspB10 Glargine R R D Aspart D Preserving structure-function relationships

  8. Self-association of insulin:monomer -> dimer -> hexamer Whittingham JL et al. Biochemistry 1998;37:11516-11523.

  9. Insulin aggregation and s.c. absorption Subcutaneous tissue 10–8 Mol/l 10–5 10–3 10–4 Diffusion Capillary membrane Adapted from Brange, Diabetes Care 1990;13:923-954.

  10. Strategies for engineering soluble basal insulins • Modify isoelectric point: precipitation at pH 7.4 • NovoSol Basal (A21Gly,B27Arg,B30ThrNH2) • Insulin glargine (A21Gly, B31B32diArg) • Strengthen hexamer association • Co(III)-hexamer • Binding to endogenous carrier proteins • Insulin detemir (Levemir®)

  11. Solubility Self-association Albumin binding Insulin detemirLysB29(N-tetradecanoyl)des(B30)human insulin C14 fatty acid (Myristic acid) Phe Gly Phe Arg Glu Tyr Thr Gly Pro Cys Lys Val Thr Lys Cys Asn A21 B29 Leu Tyr Gly A1 Asn Tyr Ile Glu Leu Val Leu Ala Glu Glu Gln Gln Tyr Val Cys Leu Leu Cys Ser Ser Thr Ile Cys His Ser Gly Cys Leu Gln His Asn Val Phe B1

  12. 3D structure of hexameric insulin Insulin detemir Human insulin

  13. Model of a di-hexamer of detemir bound to two molecules of albumin Mw ~ 206 kD

  14. In the subcutaneous depot In the circulation In the interstitium Subcutaneous depot Plasma compartment Interstitial compartment Potential sites of protraction

  15. Albumin binding buffers absorption rate changes 140 120 Absorption rate 100 80 Relative change (%) Interstitial human insulin 60 40 Interstitial detemir 20 0 Duration 0 60 120 180 240 300 360 The calculated effect of a 60-minute doubling of absorption rate on the interstitial concentrations of human insulin and insulin detemir

  16. Relative affinities of insulin detemir: receptor and albumin Conclusion: Insulin detemir has more than 10,000 fold stronger affinity for the insulin receptor than it does for albumin.

  17. I-III Albumin domains. Putative binding sites: Myr: myristic acid TIB: classic binding sites for other drugs Myristic acid binding sites Myristic acid binding site Myristic acid binding sites Distinct binding sites on albumin Curry S et al. Nature Structural Biology 1998:5:827-835.

  18. Conclusion: At therapeutic doses, insulin detemir occupies a tiny fraction of available albumin binding sites, with more than 60000-fold excess albumin over insulin Safety of albumin binding of insulin detemir

  19. Safety • Drug-drug interactions • Fluctuations in circulating FFA • Range of pH • Low plasma albumin • Proteinuria

  20. Insulin action Supra-physiological insulin concentration Insulin Insulin receptor IGF-I receptor Insulin receptor tyrosine kinase Downstream targets Metabolic effects Mitogenic effects

  21. IGF-I receptor affinity and mitogenic potency IGF-IR affinity Mitogenic potency (Saos/B10 cells) Human insulin (HI) = 100 = 100 Insulin X10 587 975 Insulin aspart 81 58 Insulin lispro 156 66 Insulin glargine 641 783 Insulin detemir 16 11 Kurtzhals P et al. Diabetes 2000;49:999-1005.

  22. In vitro mitogenicity of insulin detemir Novo Nordisk. Data on file.

  23. Insulin detemir (Levemir®) • Designed to bind specifically to albumin • Albumin binding protracts: • Absorption of insulin detemir from the subcutaneous depot • Residency of insulin detemir in the circulation • Albumin binding buffers variability of action of insulin detemir • There are no safety concerns with albumin binding of insulin detemir or with changes to its insulin structure

  24. Conclusion • Insulin detemir has pharmacological and physicochemical properties suitable for predictable basal insulin delivery

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