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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

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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

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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

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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

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In light of the observations in relation to its use in asthma, the extension of ciclosporin's 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[28] and episodes are most likely to occur in the first post-operative year.[29] 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[30][31][32] and soon thereafter in transplant patients.[6][33] Most of these early efforts were carried out by or associated with the University of Pittsburgh Medical Center.[34] A randomized, placebo-controlled trial of aerosolized ciclosporin that was published in the New England Journal of Medicine demonstrated a marked improvement in survival and reduction of chronic rejection incidence, but not in the primary endpoint of acute rejection.[35] This has warranted more detailed investigations of aerosolized drug to treat or prevent the varied conditions of rejection.

Chronic rejection

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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[36] chronic rejection appears to have significant epithelial involvement and is essentially a fibro-proliferative disorder of the small airways.[37] 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.[38] 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.[39] Early studies have also been conducted with liposome formulations in volunteers and patients.

Other

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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.[40]

References

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  1. ^ Calne, R (Mar 2004). "Cyclosporine as a milestone in immunosuppression". Transplant. Proc. 36 (2 Suppl): 13S–15S. doi:10.1016/j.transproceed.2004.01.042. PMID 15041300.
  2. ^ Madan V, Griffiths CE. "Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther. 2007 Jul-Aug;20(4):239-50.
  3. ^ Kitahara K, Kawai S. "Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2007 May;19(3):238-45. Review.
  4. ^ Ridder, WH 3rd (Dec 2008). "Ciclosporin use in dry eye disease patients". Expert Opin Pharmacother. 9 (17): 3121–8. doi:10.1517/14656560802500613. PMID 19006483. S2CID 72181779.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  5. ^ Czogalla, A (2009). "Oral cyclosporine A--the current picture of its liposomal and other delivery systems". Cell Mol Biol Lett. 14 (1): 139–52. doi:10.2478/s11658-008-0041-6. PMC 6275704. PMID 19005620.
  6. ^ a b Iacono, AT; Smaldone, GC; Keenan, RJ; Diot, P; Dauber, JH; Zeevi, A; Burckart, GJ; Griffith, BP (May 1997). "Dose-related reversal of acute lung rejection by aerosolized cyclosporine". Am J Respir Crit Care Med. 155 (5): 1690–8. doi:10.1164/ajrccm.155.5.9154878. PMID 9154878.
  7. ^ O'Riordan TG, Iacono A, Keenan RJ, Duncan SR, Burckart GJ, Griffith BP, Smaldone GC. "Delivery and distribution of aerosolized cyclosporine in lung allograft recipients. Am J Respir Crit Care Med. 1995 Feb;151 (2 Pt 1):516-21.
  8. ^ Gilbert, BE; Wilson, SZ; Garcon, NM; Wyde, PR; Knight, V (Oct 1993). "Characterization and administration of cyclosporine liposomes as a small-particle aerosol". Transplantation. 56 (4): 974–7. doi:10.1097/00007890-199310000-00037. PMID 8212222. S2CID 39895268.
  9. ^ Trammer, B; Amann, A; Haltner-Ukomadu, E; Tillmanns, S; Keller, M; Högger, P (Nov 2008). "Comparative permeability and diffusion kinetics of cyclosporine A liposomes and propylene glycol solution from human lung tissue into human blood ex vivo". Eur J Pharm Biopharm. 70 (3): 758–64. doi:10.1016/j.ejpb.2008.07.001. PMID 18656538.
  10. ^ Tam, JM; McConville, JT; Williams, RO; Johnston, KP (Nov 2008). "Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution". J Pharm Sci. 97 (11): 4915–33. doi:10.1002/jps.21367. PMID 18351641.
  11. ^ Fukaya, H; Iimura, A; Hoshiko, K; Fuyumuro, T; Noji, S; Nabeshima, T (Aug 2003). "A cyclosporin A/maltosyl-alpha-cyclodextrin complex for inhalation therapy of asthma". Eur Respir J. 22 (2): 213–9. doi:10.1183/09031936.03.00018202. PMID 12952250. S2CID 73731983.
  12. ^ Zijlstra, GS; Rijkeboer, M; Jan; van Drooge, D; Sutter, M; Jiskoot, W; de Weert, M; Hinrichs, WL; Frijlink, HW (Jun 2007). "Characterization of a cyclosporine solid dispersion for inhalation". AAPS J. 9 (2): E190–9. doi:10.1208/aapsj0902021. PMC 2751408. PMID 17614361.
  13. ^ Myrdal, PB; Karlage, KL; Stein, SW; Brown, BA; Haynes, A (Apr 2004). "Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane-based metered dose inhalers". J Pharm Sci. 93 (4): 1054–61. doi:10.1002/jps.20025. PMID 14999741.
  14. ^ Marijani, R; Shaik, MS; Chatterjee, A; Singh, M (Jan 2007). "Evaluation of metered dose inhaler (MDI) formulations of ciclosporin". J Pharm Pharmacol. 59 (1): 15–21. doi:10.1211/jpp.59.1.0003. PMID 17227616. S2CID 24608166.
  15. ^ Evans, DJ; Cullinan, P; Geddes, DM (2001). "Cyclosporin as an oral corticosteroid sparing agent in stable asthma". Cochrane Database Syst Rev. 2010 (2): CD002993. doi:10.1002/14651858.CD002993. PMC 8407285. PMID 11406057.
  16. ^ Lock, SH; Kay, AB; Barnes, NC (Feb 1996). "Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma". Am J Respir Crit Care Med. 153 (2): 509–14. doi:10.1164/ajrccm.153.2.8564089. PMID 8564089.
  17. ^ Larché M, Robinson DS, Kay AB. "The role of T lymphocytes in the pathogenesis of asthma" J Allergy Clin Immunol 2003 Mar;111(3):450-63; quiz 464.
  18. ^ Alexander, AG; Barnes, NC; Kay, AB; Corrigan, CJ (Apr 1995). "Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations". Eur Respir J. 8 (4): 574–8. doi:10.1183/09031936.95.08040574. PMID 7664856. S2CID 18489547.
  19. ^ Ezeamuzie, CI; Nwankwoala, RN (Jul 2000). "Allergen-induced bronchial eosinophilia in guinea-pigs is inhibited by both pre- and post-induction cyclosporin-A treatments". Int J Immunopharmacol. 22 (7): 515–22. doi:10.1016/s0192-0561(00)00015-1. PMID 10785548.
  20. ^ Khan LN, Kon OM, Macfarlane AJ, Meng Q, Ying S, Barnes NC, Kay AB. "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.
  21. ^ Kay, AB (May 1994). "Immunosuppressive agents in chronic severe asthma". Allergy Proc. 15 (3): 147–50. doi:10.2500/108854194778702838. PMID 7523242.
  22. ^ Katz, A; Coran, AG; Oldham, KT; Guice, KS (Jun 1993). "Decreased oxidized glutathione with aerosolized cyclosporine delivery" (PDF). J Surg Res. 54 (6): 597–602. doi:10.1006/jsre.1993.1091. hdl:2027.42/30777. PMID 8412070.
  23. ^ Xie, QM; Chen, JQ; Shen, WH; Yang, QH; Bian, RL (Mar 2002). "Effects of cyclosporin A by aerosol on airway hyperresponsiveness and inflammation in guinea pigs". Acta Pharmacol. Sin. 23 (3): 243–7. PMID 11918849.
  24. ^ Arima, M; Yukawa, T; Terashi, Y; Makino, S (Dec 1994). "Effect of inhaled cyclosporin A on the allergen-induced late asthmatic response and increased in airway hyperresponsiveness in a guinea pig model of asthma". Arerugi. 43 (11): 1316–25. PMID 7887807.
  25. ^ Rohatagi, S; Calic, F; Harding, N; Ozoux, ML; Bouriot, JP; Kirkesseli, S; DeLeij, L; Jensen, BK (Nov 2000). "Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients". J Clin Pharmacol. 40 (11): 1211–26. doi:10.1177/009127000004001106. PMID 11075307. S2CID 10004392.
  26. ^ Gaga, M; Zervas, E; Grivas, S; Castro, M; Chanez, P (2007). "Evaluation and management of severe asthma". Curr. Med. Chem. 14 (9): 1049–59. doi:10.2174/092986707780362961. PMID 17439402.
  27. ^ Barnes, PJ (Aug 1996). "Immunomodulation as asthma therapy: where do we stand?". Eur Respir J Suppl. 22: 154S–159S. PMID 8871062.
  28. ^ Arcasoy, SM (Dec 2004). "Medical complications and management of lung transplant recipients". Respir Care Clin N Am. 10 (4): 505–29. doi:10.1016/j.rcc.2004.06.002. PMID 15585180.
  29. ^ Bando, K; Paradis, IL; Komatsu, K; Konishi, H; Matsushima, M; Keena, RJ; Hardesty, RL; Armitage, JM; Griffith, BP (Jan 1995). "Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation". J Thorac Cardiovasc Surg. 109 (1): 49–57. doi:10.1016/s0022-5223(95)70419-1. PMID 7815807.
  30. ^ Dowling, RD; Zenati, M; Burckart, GJ; Yousem, SA; Schaper, M; Simmons, RL; Hardesty, RL; Griffith, BP (Aug 1990). "Aerosolized cyclosporine as single-agent immunotherapy in canine lung allografts". Surgery. 108 (2): 198–204. PMID 2382220.
  31. ^ Keenan, RJ; Duncan, AJ; Yousem, SA; Zenati, M; Schaper, M; Dowling, RD; Alarie, Y; Burckart, GJ; Griffith, BP (Jan 1992). "Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation". Transplantation. 53 (1): 20–5. doi:10.1097/00007890-199201000-00003. PMID 1733067. S2CID 12010964.
  32. ^ Blot F, Tavakoli R, Sellam S, Epardeau B, Faurisson F, Bernard N, Becquemin MH, Frachon I, Stern M, Pocidalo JJ, et al. "Nebulized cyclosporine for prevention of acute pulmonary allograft rejection in the rat: pharmacokinetic and histologic study. J Heart Lung Transplant. 1995 Nov-Dec;14 (6 Pt 1):1162-72.
  33. ^ Keenan, RJ; Iacono, A; Dauber, JH; Zeevi, A; Yousem, SA; Ohori, NP; Burckart, GJ; Kawai, A; Smaldone, GC; Griffith, BP (Feb 1997). "Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients". J Thorac Cardiovasc Surg. 113 (2): 335–40. doi:10.1016/s0022-5223(97)70331-3. PMID 9040628.
  34. ^ McCurry, KR; Iacono, AT; Dauber, JH; Grgurich, WF; Pham, SM; Hattler, BG; Keenan, RJ; Griffith, BP. "Lung and heart-lung transplantation at the University of Pittsburgh". Clin Transpl. 1997: 209–18.
  35. ^ 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 (Jan 2006). "A randomized trial of inhaled cyclosporine in lung-transplant recipients". N Engl J Med. 354 (2): 141–50. doi:10.1056/nejmoa043204. PMID 16407509. S2CID 33787892.
  36. ^ Martinu, T; Chen, DF; Palmer, SM (Jan 2009). "Acute rejection and humoral sensitization in lung transplant recipients". Proceedings of the American Thoracic Society. 6 (1): 54–65. doi:10.1513/pats.200808-080go. PMC 2626504. PMID 19131531.
  37. ^ Belperio, JA; Weigt, SS; Fishbein, MC; Lynch, JP (Jan 2009). "Chronic lung allograft rejection: mechanisms and therapy". Proceedings of the American Thoracic Society. 6 (1): 108–21. doi:10.1513/pats.200807-073go. PMID 19131536. S2CID 23071315.
  38. ^ Orens, JB; Garrity, ER Jr (Jan 2009). "General overview of lung transplantation and review of organ allocation". Proceedings of the American Thoracic Society. 6 (1): 13–9. doi:10.1513/pats.200807-072go. PMID 19131526.
  39. ^ "Ciclosporin clinical trials". Clinicaltrials.gov. Retrieved 3 June 2011.
  40. ^ Knight, V; Koshkina, NV; Golunski, E; Roberts, LE; Gilbert, BE (2004). "Cyclosporin an aerosol improves the anticancer effect of Paclitaxel aerosol in mice". Trans Am Clin Climatol Assoc. 115: 395–404. PMC 2263789. PMID 17060982.
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