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The Preclinical Pharmacology of Indacaterol

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Indacaterol

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

The preclinical pharmacological profile of indacaterol, a novel, chirally pure inhaled beta(2) adrenoceptor agonist, is described in this chapter. In various in vitro systems, indacaterol is close to a full agonist at the human β2-adrenoceptor with nanomolar potency. In isolated superfused human and guinea pig trachea, indacaterol has a fast onset of and a long duration of action. In the conscious guinea pig, when given intratracheally as a dry powder, indacaterol inhibits bronchoconstriction for at least 24 h and shows no tachyphylaxis when given for 5 consecutive days. When given via nebulization to anesthetized rhesus monkeys, indacaterol produces a prolonged bronchoprotective effect and induces a small increase in heart rate. In in vitro systems as well as a large cohort of COPD patients, no association could be demonstrated between β2-adrenoceptor polymorphisms and indacaterol response. In conclusion, the preclinical profile of indacaterol suggests that this compound has a duration of action compatible with once-daily dosing in human, together with a fast onset of action.

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References

  1. Cazzola M, Matera MG (2008) Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol 155:291–9

    Article  PubMed  CAS  Google Scholar 

  2. Alexander SP, Mathie A, Peters JA (2008) Guide to receptors and channels (GRAC), 3rd edition. Br J Pharmacol 153(Suppl 2):S1–209

    Article  PubMed  Google Scholar 

  3. Giembycz MA, Newton R (2006) Beyond the dogma: novel β2-adrenoceptor signalling in the airways. Eur Respir J 27:1286–306

    Article  PubMed  CAS  Google Scholar 

  4. Battram C, Charlton SJ, Cuenoud B, Dowling MR, Fairhurst RA, Farr D, Fozard JR, Leighton-Davies JR, Lewis CA, McEvoy L, Turner RJ, Trifilieff A (2006) In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quino lin-2-one (indacaterol), a novel inhaled beta(2) adrenoceptor agonist with a 24-h duration of action. J Pharmacol Exp Ther 317:762–70

    Article  PubMed  CAS  Google Scholar 

  5. Sayers I, Hawley J, Stewart CE, Billington CK, Henry A, Leighton-Davies JR, Charlton SJ, Hall IP (2009) Pharmacogenetic characterization of indacaterol, a novel beta 2-adrenoceptor agonist. Br J Pharmacol 158:277–86

    Article  PubMed  CAS  Google Scholar 

  6. Duringer C, Grundstrom G, Gurcan E, Dainty IA, Lawson M, Korn SH, Jerre A, Hakansson HF, Wieslander E, Fredriksson K, Skold CM, Lofdahl M, Lofdahl CG, Nicholls DJ, Silberstein DS (2009) Agonist-specific patterns of beta 2-adrenoceptor responses in human airway cells during prolonged exposure. Br J Pharmacol 158:169–79

    Article  PubMed  Google Scholar 

  7. Rosethorne EM, Turner RJ, Fairhurst RA, Charlton SJ (2010) Efficacy is a contributing factor to the clinical onset of bronchodilation of inhaled beta(2)-adrenoceptor agonists. Naunyn Schmiedebergs Arch Pharmacol 382:255–63

    Article  PubMed  CAS  Google Scholar 

  8. Scola AM, Loxham M, Charlton SJ, Peachell PT (2009) The long-acting beta-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cells. Br J Pharmacol 158:267–76

    Article  PubMed  CAS  Google Scholar 

  9. Marchese A, Paing MM, Temple BR, Trejo J (2008) G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol 48:601–29

    Article  PubMed  CAS  Google Scholar 

  10. Clark RB, Knoll BJ, Barber R (1999) Partial agonists and G protein-coupled receptor desensitization. Trends Pharmacol Sci 20(7):279–86

    Article  PubMed  CAS  Google Scholar 

  11. January B, Seibold A, Whaley B, Hipkin RW, Lin D, Schonbrunn A et al (1997) beta(2)-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists. J Biol Chem 272:23871–9

    Article  PubMed  CAS  Google Scholar 

  12. Charlton SJ (2009) Agonist efficacy and receptor desensitization: from partial truths to a fuller picture. Br J Pharmacol 158(1):165–8

    Article  PubMed  CAS  Google Scholar 

  13. Waldeck B (1976) An in vitro method for the study of beta-receptor mediated effects on slow contracting skeletal muscle. J Pharm Pharmacol 28:434–6

    Article  PubMed  CAS  Google Scholar 

  14. Haffner CA, Kendall MJ (1992) Metabolic effects of beta 2-agonists. J Clin Pharm Ther 17:155–64

    Article  PubMed  CAS  Google Scholar 

  15. Cazzola M, Matera MG, Donner CF (2005) Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs 65:1595–610

    Article  PubMed  CAS  Google Scholar 

  16. Molenaar P, Chen L, Semmler AB, Parsonage WA, Kaumann AJ (2007) Human heart beta-adrenoceptors: beta1-adrenoceptor diversification through ‘affinity states’ and polymorphism. Clin Exp Pharmacol Physiol 34:1020–8

    Article  PubMed  CAS  Google Scholar 

  17. Levine MA, Leenen FH (1989) Role of beta 1-receptors and vagal tone in cardiac inotropic and chronotropic responses to a beta 2-agonist in humans. Circulation 79:107–15

    Article  PubMed  CAS  Google Scholar 

  18. Brookman LJ, Knowles LJ, Barbier M, Elharrar B, Fuhr R, Pascoe S (2007) Efficacy and safety of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and salbutamol in patients with asthma. Curr Med Res Opin 23:3113–22

    Article  PubMed  CAS  Google Scholar 

  19. Motomura S, Reinhard-Zerkowski H, Daul A, Brodde OE (1990) On the physiologic role of beta-2 adrenoceptors in the human heart: in vitro and in vivo studies. Am Heart J 119:608–19

    Article  PubMed  CAS  Google Scholar 

  20. Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Avier-Klutchko C, Strosberg AD (1989) Molecular characterization of the human beta 3-adrenergic receptor. Science 245:1118–21

    Article  PubMed  CAS  Google Scholar 

  21. Ursino MG, Vasina V, Raschi E, Crema F, De PF (2009) The beta3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 59:221–34

    Article  PubMed  CAS  Google Scholar 

  22. van Noord JA, Smeets JJ, Raaijmakers JA, Bommer AM, Maesen FP (1996) Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Eur Respir J 9:1684–8

    Article  PubMed  Google Scholar 

  23. Rennard S, Bantje T, Centanni S, Chanez P, Chuchalin A, D’Urzo A, Kornmann O, Perry S, Jack D, Owen R, Higgins M (2008) A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison. Respir Med 102:1033–44

    Article  PubMed  Google Scholar 

  24. Balint B, Watz H, Amos C, Owen R, Higgins M, Kramer B (2010) Onset of action of indacaterol in patients with COPD: comparison with salbutamol and salmeterol-fluticasone. Int J Chron Obstruct Pulmon Dis 5:311–8

    PubMed  CAS  Google Scholar 

  25. Charles MS, Blanchette CM, Silver H, Lavallee D, Dalal AA, Mapel D (2010) Adherence to controller therapy for chronic obstructive pulmonary disease: a review. Curr Med Res Opin 26:2421–9

    Article  PubMed  Google Scholar 

  26. Han MK (2009) Medication adherence in COPD: what have we learned? Thorax 64:922–3

    Article  PubMed  Google Scholar 

  27. Horne R (2006) Compliance, adherence, and concordance: implications for asthma treatment. Chest 130:65S–72

    Article  PubMed  Google Scholar 

  28. Partridge MR, Miravitlles M, Stahl E, Karlsson N, Svensson K, Welte T (2010) Development and validation of the capacity of daily living during the morning and global chest symptoms questionnaires in COPD. Eur Respir J 36(1):96–104

    Article  PubMed  CAS  Google Scholar 

  29. Partridge MR, Karlsson N, Small IR (2009) Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin 25:2043–8

    Article  PubMed  Google Scholar 

  30. Partridge MR, Schuermann W, Beckman O, Persson T, Polanowski T (2009) Effect on lung function and morning activities of budesonide/formoterol versus salmeterol/fluticasone in patients with COPD. Ther Adv Respir Dis 3:1–11

    Article  PubMed  Google Scholar 

  31. Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M (2007) Effect of indacaterol, a novel long-acting β2-agonist, on isolated human bronchi. Eur Respir J 29:575–81

    Article  PubMed  CAS  Google Scholar 

  32. Sturton RG, Trifilieff A, Nicholson AG, Barnes PJ (2008) Pharmacological characterization of indacaterol, a novel once daily inhaled 2 adrenoceptor agonist, on small airways in human and rat precision-cut lung slices. J Pharmacol Exp Ther 324:270–5

    Article  PubMed  CAS  Google Scholar 

  33. Anderson GP, Linden A, Rabe KF (1994) Why are long-lasting β2-adrenoceptor agonists long-lasting? Eur Respir J 7:569–78

    Article  PubMed  CAS  Google Scholar 

  34. Baur F, Beattie D, Beer D, Bentley D, Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T, Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C, Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M, Watson S, Wissler E, Wyss D (2010) The identification of indacaterol as an ultra-long-acting inhaled β2-adrenoceptor agonist. J Med Chem 53:3675–84

    Article  PubMed  CAS  Google Scholar 

  35. Rhodes DG, Newton R, Butler R, Herbette L (1992) Equilibrium and kinetic studies of the interactions of salmeterol with membrane bilayers. Mol Pharmacol 4:596–602

    Google Scholar 

  36. Lombardi D, Cuenoud B, Kramer SD (2009) Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties? Eur J Pharm Sci 38:533–47

    Article  PubMed  CAS  Google Scholar 

  37. Sykes DA, Charlton SJ (2012) Slow dissociation from receptors is not a key factor in the duration of action of inhaled long acting β2-adrenoceptor agonists. Br J Pharmacol 165(8):2672–83

    Article  PubMed  CAS  Google Scholar 

  38. Sin DD (2004) Therapeutic options for chronic obstructive pulmonary disease: present and future. Eur Rev Med Pharmacol Sci 8:247–58

    PubMed  CAS  Google Scholar 

  39. Sutherland ER (2004) Outpatient treatment of chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol 114:715–24

    Article  PubMed  Google Scholar 

  40. Koumis T, Samuel S (2005) Tiotropium bromide: a new long-acting bronchodilator for the treatment of chronic obstructive pulmonary disease. Clin Ther 27:377–92

    Article  PubMed  CAS  Google Scholar 

  41. Summerhill S, Stroud T, Nagendra R, Perros-Huguet C, Trevethick M (2008) A cell-based assay to assess the persistence of action of agonists acting at recombinant human beta(2) adrenoceptors. J Pharmacol Toxicol Methods 58:189–97

    Article  PubMed  CAS  Google Scholar 

  42. McNamara A, Pulido-Rios MT, Hegde SS, Martin WJ (2011) Application of the classical Einthoven model of bronchoconstriction to the study of inhaled bronchodilators in rodents. J Pharmacol Toxicol Methods 63(1):89–95

    Article  PubMed  CAS  Google Scholar 

  43. Disse B, Speck GA, Rominger KL, Witek TJ Jr, Hammer R (1999) Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 64:457–64

    Article  PubMed  CAS  Google Scholar 

  44. Voss HP, Donnell D, Bast A (1992) Atypical molecular pharmacology of a new long-acting beta 2-adrenoceptor agonist, TA 2005. Eur J Pharmacol 227:403–9

    Article  PubMed  CAS  Google Scholar 

  45. Szczuka A, Wennerberg M, Packeu A, Vauquelin G (2009) Molecular mechanisms for the persistent bronchodilatory effect of the beta 2-adrenoceptor agonist salmeterol. Br J Pharmacol 158(1):183–94

    Article  PubMed  CAS  Google Scholar 

  46. Vauquelin G, Charlton SJ (2010) Long-lasting target binding and rebinding as mechanisms to prolong in vivo drug action. Br J Pharmacol 161(3):488–508

    Article  PubMed  CAS  Google Scholar 

  47. Battram C, Li J, Coulthard A, Hardaker L, Poll C, Askey-Sarvar A, Trifilieff A (2009) Indacaterol does not blunt the effect of salbutamol in vivo. Am J Respir Crit Care Med 179:A2075

    Google Scholar 

  48. Hawkins GA, Weiss ST, Bleecker ER (2008) Clinical consequences of ADRbeta2 polymorphisms. Pharmacogenomics 9:349–58

    Article  PubMed  CAS  Google Scholar 

  49. Yelenski R, Li Y, Lewitzky S, Leroy E, Hurwitz C, Rodman D, Trifilieff A, Paulding CA (2012) A pharmacogenetic study of ADRB2 polymorphisms and indacaterol response in COPD Patients. Pharmacogenomics J 12:484–8

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Alexandre Trifilieff & Robin A. Fairhurst

  2. Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, RH12 5AB, UK

    Steven J. Charlton

Authors
  1. Alexandre Trifilieff
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  2. Steven J. Charlton
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  3. Robin A. Fairhurst
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Corresponding author

Correspondence to Steven J. Charlton .

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Editors and Affiliations

  1. Respiratory Diseases Area, Novartis Institutes for BioMedical Reseach, Basel, Switzerland

    Alexandre Trifilieff

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Trifilieff, A., Charlton, S.J., Fairhurst, R.A. (2014). The Preclinical Pharmacology of Indacaterol. In: Trifilieff, A. (eds) Indacaterol. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0348-0709-8_2

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