Inhaled ciclosporin

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Ciclosporin is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant.[1] It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis,[2] rheumatoid arthritis,[3] dry eye[4] and other auto-immune related conditions. A variety of pre-clinical and clinical studies have been and are investigating its use to treat lung-related disorders via inhalation.

Formulation

Formulation of the drug for inhalation purposes has proved challenging because of ciclosporin's poor aqueous solubility.[5] Consequently, aerosol studies have often employed compatible solvents such as propylene glycol[6] or ethanol[7] as the vehicle for administration by nebulizer or have used more complicated aqueous-based formulations involving liposomes [8][9] or other dispersions.[10] Dry powder inhaler [11][12] as well as propellant metered dose inhaler (pMDI) formulations [13][14] have also been created and evaluated in the laboratory and in early clinical studies.

Investigational uses

Ciclosporin was brought to market in 1983 but the first non human aerosol studies were not published until the late 1980s. These efforts probed the anti-inflammatory and immunosuppressive properties of ciclosporin after regional deposition of drug in the lungs.

Asthma

Ciclosporin has been touted as a therapeutic option in moderate to severe asthmatic patients[15] as a corticosteroid sparing agent.[16] Preclinical studies bear evidence to the fact that ciclosporin when administered orally or via inhalation is capable of blocking T-cell induced inflammation (e.g. via interleukin-2 and 13 formation).,[17][18] eosinophil[19][20] and macrophage recruitment in the lungs. Its use to treat asthma via the oral route may be constrained by systemic side-effects [21] but this limitation may be avoided by targeting the lungs with therapeutic doses via inhalation. Pharmacokinetic evidence suggests that peak and trough levels of drug in the circulation are likely to be below the threshold of systemic toxicity.[22] In addition to biomarkers inhaled ciclosporin has been shown to inhibit airway hyperresponsiveness in rodent models[23][24] and appears to have been well tolerated in volunteers and mild asthmatic patients receiving the drug in single and multiple doses via pMDI.[25] However, as of early 2009 there are no ongoing clinical trials further exploring ciclosporin's utility in asthma; in part, this may be a consequence of sporadic efficacy and side-effects (from oral use) in a condition that is historically managed by steroids.[26][27]

Acute rejection

Given ciclosporin's success in managing acute rejection of kidney[28] and liver transplants,[29] the extension of its use to treat early rejection in the lungs was an obvious one especially considering the increase in lung transplants performed in the USA and Europe since the mid-1980s. Numbers have increased from 33 in 1988 to 1468 in 2007. Furthermore, acute cellular rejection is common after transplantation and will occur in up to 90% of patients[30] and episodes are most likely to occur in the first post-operative year.[31] Consequently, the application of ciclosporin by oral and IV administration has led to efforts to treat acute and acute refractory rejection by direct aerosol administration first in animal models [32][33][34] and soon thereafter in transplant patients.[6][35] Most of these early efforts were carried out by or associated with the University of Pittsburgh Medical Center.[36] Unfortunately, the apparent success of aerosolized ciclosporin in animal studies and these early clinical studies was not duplicated in a subsequent randomized, placebo-controlled trial of aerosolized ciclosporin that was published in the New England Journal of Medicine.[37] Nevertheless, a robust effect was noted in chronic rejection and survival and this has warranted more detailed investigations of aerosolized drug to treat or prevent the varied conditions of rejection.

Chronic rejection

Chronic rejection of the lungs differs significantly from acute rejection. The condition is aptly known as bronchiolitis obliterans and clinically is diagnosed as bronchiolitis obliterans syndrome (BOS). Whereas acute rejection exhibits perivascular infiltration of mononuclear cells and attendant inflammation of the surrounding tissue [38] chronic rejection appears to have significant epithelial involvement and is essentially a fibro-proliferative disorder of the small airways.[39] Sadly, the median survival after a confirmed diagnosis of BOS is just over 2 years. In fact, despite improvements in outcome associated with acute rejection, virtually no improvement in survival has been noted in chronic rejection over the last 20 years.[40] The surprising finding that aerosolized ciclosporin may prevent or delay development of this insidious condition has led to renewed interest with aerosolized ciclosporin formulations and one early stage trial involving a dry powder inhaler is recruiting while another phase III trial involving nebulized ciclosporin in propylene glycol is underway.[41] Early studies have also been conducted with liposome formulations in volunteers and patients.

Other

Inhaled ciclosporin has also shown promise in several other lung conditions. Early stage studies in mice have shown some benefit of ciclosporin as an adjuvant therapy in lung cancer when administered as a liposome aerosol in conjunction with paclitaxel.[42]

References

  1. ↑ Cyclosporine as a milestone in immunosuppression. Calne R. Transplant Proc. 2004 Mar;36(2 Suppl):13S-15S
  2. ↑ Systemic ciclosporin and tacrolimus in dermatology. Madan V, Griffiths CE. Dermatol Ther. 2007 Jul-Aug;20(4):239-50. Review.
  3. ↑ Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Kitahara K, Kawai S. Curr Opin Rheumatol. 2007 May;19(3):238-45. Review.
  4. ↑ Ciclosporin use in dry eye disease patients. Ridder WH 3rd. Expert Opin Pharmacother. 2008 Dec;9(17):3121-8.
  5. ↑ Oral cyclosporine A--the current picture of its liposomal and other delivery systems. Czogalla A. Cell Mol Biol Lett. 2009;14(1):139-52. Epub 2008 Nov 12. Review
  6. ↑ 6.0 6.1 Dose-related reversal of acute lung rejection by aerosolized cyclosporine. Iacono AT, Smaldone GC, Keenan RJ, Diot P, Dauber JH, Zeevi A, Burckart GJ, Griffith BP. Am J Respir Crit Care Med. 1997 May;155(5):1690-8.
  7. ↑ Delivery and distribution of aerosolized cyclosporine in lung allograft recipients. O'Riordan TG, Iacono A, Keenan RJ, Duncan SR, Burckart GJ, Griffith BP, Smaldone GC. Am J Respir Crit Care Med. 1995 Feb;151 (2 Pt 1):516-21.
  8. ↑ Characterization and administration of cyclosporine liposomes as a small-particle aerosol. Gilbert BE, Wilson SZ, Garcon NM, Wyde PR, Knight V. Transplantation. 1993 Oct;56(4):974-7.
  9. ↑ Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo. Trammer B, Amann A, Haltner-Ukomadu E, Tillmanns S, Keller M, Högger P. Eur J Pharm Biopharm. 2008 Nov;70(3):758-64. Epub 2008
  10. ↑ Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution. Tam JM, McConville JT, Williams RO 3rd, Johnston KP. J Pharm Sci. 2008 Nov;97(11):4915-33.
  11. ↑ Eur Respir J. 2003 Aug;22(2):213-9. A cyclosporin A/maltosyl-alpha-cyclodextrin complex for inhalation therapy of asthma. Fukaya H, Iimura A, Hoshiko K, Fuyumuro T, Noji S, Nabeshima T.
  12. ↑ Characterization of a cyclosporine solid dispersion for inhalation. Zijlstra GS, Rijkeboer M, Jan van Drooge D, Sutter M, Jiskoot W, van de Weert M, Hinrichs WL, Frijlink HW. AAPS J. 2007 Jun 15;9(2):E190-9.
  13. ↑ Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane-based metered dose inhalers. Myrdal PB, Karlage KL, Stein SW, Brown BA, Haynes A. J Pharm Sci. 2004 Apr;93(4):1054-61.
  14. ↑ Evaluation of metered dose inhaler (MDI) formulations of ciclosporin. Marijani R, Shaik MS, Chatterjee A, Singh M. J Pharm Pharmacol. 2007 Jan;59(1):15-21
  15. ↑ Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Evans DJ, Cullinan P, Geddes DM. Cochrane Database Syst Rev. 2001;(2):CD002993.
  16. ↑ Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Lock SH, Kay AB, Barnes NC. Am J Respir Crit Care Med. 1996 Feb;153(2):509-14.
  17. ↑ The role of T lymphocytes in the pathogenesis of asthma. Larché M, Robinson DS, Kay AB. J Allergy Clin Immunol. 2003 Mar;111(3):450-63; quiz 464.
  18. ↑ Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations Alexander AG, Barnes NC, Kay AB, Corrigan CJ. Eur Respir J. 1995 Apr;8(4):574-8..
  19. ↑ Allergen-induced bronchial eosinophilia in guinea-pigs is inhibited by both pre- and post-induction cyclosporin-A treatments. Ezeamuzie CI, Nwankwoala RN. Int J Immunopharmacol. 2000 Jul;22(7):515-22.
  20. ↑ Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor, and eotaxin. Khan LN, Kon OM, Macfarlane AJ, Meng Q, Ying S, Barnes NC, Kay AB.
  21. ↑ Immunosuppressive agents in chronic severe asthma. Kay AB. Allergy Proc. 1994 May-Jun;15(3):147-50. Review.
  22. ↑ Decreased oxidized glutathione with aerosolized cyclosporine delivery. Katz A, Coran AG, Oldham KT, Guice KS. J Surg Res. 1993 Jun;54(6):597-602.
  23. ↑ Effects of cyclosporin A by aerosol on airway hyperresponsiveness and inflammation in guinea pigs. Xie QM, Chen JQ, Shen WH, Yang QH, Bian RL. Acta Pharmacol Sin. 2002 Mar;23(3):243-7.
  24. ↑ Effect of inhaled cyclosporin A on the allergen-induced late asthmatic response and increased in airway hyperresponsiveness in a guinea pig model of asthma Arima M, Yukawa T, Terashi Y, Makino S. Arerugi. 1994 Dec;43(11):1316-25.
  25. ↑ Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients. Rohatagi S, Calic F, Harding N, Ozoux ML, Bouriot JP, Kirkesseli S, DeLeij L, Jensen BK. J Clin Pharmacol. 2000 Nov;40(11):1211-26.
  26. ↑ Evaluation and management of severe asthma. Gaga M, Zervas E, Grivas S, Castro M, Chanez P. Curr Med Chem. 2007;14(9):1049-59. Review.
  27. ↑ Immunomodulation as asthma therapy: where do we stand? Barnes PJ. Eur Respir J Suppl. 1996 Aug;22:154s-159s. Review.
  28. ↑ The use of cyclosporine in renal transplantation. Transplant Proc. 2004 Mar;36 (2 Suppl):99S-106S. Hesselink DA, Smak Gregoor PJ, Weimar W.
  29. ↑ Impact of cyclosporine on the development of immunosuppressive therapy in liver transplantation. Casanovas Taltavull T. Transplant Proc. 2004 Mar;36 (2 Suppl):291S-294S. Review.
  30. ↑ Medical complications and management of lung transplant recipients. Arcasoy SM. Respir Care Clin N Am. 2004 Dec;10(4):505-29. Review.
  31. ↑ Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation. Bando K, Paradis IL, Komatsu K, Konishi H, Matsushima M, Keena RJ, Hardesty RL, Armitage JM, Griffith BP. J Thorac Cardiovasc Surg. 1995 Jan;109(1):49-57; discussion 57-9.
  32. ↑ Aerosolized cyclosporine as single-agent immunotherapy in canine lung allografts. Dowling RD, Zenati M, Burckart GJ, Yousem SA, Schaper M, Simmons RL, Hardesty RL, Griffith BP. Surgery. 1990 Aug;108(2):198-204; discussion 204-5.
  33. ↑ Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation. Keenan RJ, Duncan AJ, Yousem SA, Zenati M, Schaper M, Dowling RD, Alarie Y, Burckart GJ, Griffith BP. Transplantation. 1992 Jan;53(1):20-5.
  34. ↑ Nebulized cyclosporine for prevention of acute pulmonary allograft rejection in the rat: pharmacokinetic and histologic study. Blot F, Tavakoli R, Sellam S, Epardeau B, Faurisson F, Bernard N, Becquemin MH, Frachon I, Stern M, Pocidalo JJ, et al. J Heart Lung Transplant. 1995 Nov-Dec;14 (6 Pt 1):1162-72.
  35. ↑ Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients. Keenan RJ, Iacono A, Dauber JH, Zeevi A, Yousem SA, Ohori NP, Burckart GJ, Kawai A, Smaldone GC, Griffith BP. J Thorac Cardiovasc Surg. 1997 Feb;113(2):335-40; discussion 340-1.
  36. ↑ Clin Transpl. 1997:209-18. Lung and heart-lung transplantation at the University of Pittsburgh. McCurry KR, Iacono AT, Dauber JH, Grgurich WF, Pham SM, Hattler BG, Keenan RJ, Griffith BP
  37. ↑ A randomized trial of inhaled cyclosporine in lung-transplant recipients. Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, Griffith BP. N Engl J Med. 2006 Jan 12;354(2):141-50.
  38. ↑ Acute rejection and humoral sensitization in lung transplant recipients. Martinu T, Chen DF, Palmer SM. Proc Am Thorac Soc. 2009 Jan 15;6(1):54-65.
  39. ↑ Chronic lung allograft rejection: mechanisms and therapy. Belperio JA, Weigt SS, Fishbein MC, Lynch JP 3rd. Proc Am Thorac Soc. 2009 Jan 15;6(1):108-21.
  40. ↑ General overview of lung transplantation and review of organ allocation. Orens JB, Garrity ER Jr. Proc Am Thorac Soc. 2009 Jan 15;6(1):13-9.
  41. ↑ "Ciclosporin clinical trials". Clinicaltrials.gov. Retrieved 3 June 2011. 
  42. ↑ Cyclosporin an aerosol improves the anticancer effect of Paclitaxel aerosol in mice. Knight V, Koshkina NV, Golunski E, Roberts LE, Gilbert BE. Trans Am Clin Climatol Assoc. 2004;115:395-404.

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