Asthma Knowledge Centre
Alvesco
Pharmacodynamics - Targeted deposition and activation
Formulation
Alvesco is formulated as a solution, which is delivered via a HFA–MDI. Typically, HFA–MDIs deliver a higher proportion of the dose to the lung than the older CFC–MDI formulations.1,2 As a solution formulation, Alvesco generates extra-fine particles (particle size 1.1–2.1 µm)3,4 that result in high pulmonary deposition and distribution throughout the lungs, including penetration of the small airways,5,6 as well as a low potential for local adverse events due to reduced oropharyngeal deposition.5,6,
High pulmonary deposition and activation
The high pulmonary deposition of Alvesco was shown in two separate studies using γ-scintigraphy after inhalation of a single dose of Technetium 99m-labeled Alvesco by healthy subjects.5,7 The studies showed that approximately 52% of the Alvesco dose was deposited in the lung.5,6 3-D imaging showed that 47% of the Alvesco dose penetrated into the peripheral airways (Figure 1).7 High pulmonary deposition increases the concentration of drug able to exert local anti-inflammatory action.
“Alvesco is formulated as a solution and delivered by HFA–MDI, providing extra-fine particles resulting in high pulmonary deposition, including peripheral airway penetration.3,7
Figure 1. Deposition of Alvesco following inhalation
Reproduced with permission from Leach C, Bethke T, Boudreau R. 2-D and 3-D imaging show ciclesonide has high lung deposition andperipheral distribution: a nonrandomized study in healthy volunteers. J Aerosol Med 2006; 19:117–126. Copyright Mary Ann Liebert, Inc,. 2006. All rights reserved.
Activation of Alvesco to a potent anti-inflammatory glucocorticoid (des-CIC) occurs rapidly in vitro in bronchial epithelial cells and in vivo within the lung.8,9,10,11 In cultured human bronchial epithelial cells incubated with 5 µM Alvesco, Alvesco was rapidly hydrolyzed by carboxylesterases (major contributor) and cholinesterases (minor contributor) to des-CIC; approximately 30% was converted at 4 hours and nearly 100% was converted by 24 hours. Preincubation with esterase inhibitors reduced conversion of Alvesco to des-CIC.10
For Alvesco prescribing information please refer to full Summary of Product Characteristics
Disclaimer: For exclusive use at EPG Asthma Knowledge Centre, July 2008. Local regulation may apply. Please check your local SmPC.
References:
1. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Saf 2000;23:11–33.
2. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers. Chest 2002;122:510–516.
3. Derendorf H, Nave R, Drollmann A, Cerasoli F, Wurst W. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J 2006;28:1042–1050.
4. Rohatagi S, Derendorf H, Zech K, Nave R, Banerji D. PK/PD of inhaled corticosteroids: the risk/benefit of inhaled ciclesonide. J Allergy Clin Immunol 2003;111:S380 (abstract 598).
5. Leach CL, Bethke TD, Boudreau RJ, Hasselquist BE, Drollmann A, Davidson P, et al. Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers. J Aerosol Med 2006;19:117–126.
6. Newman S, Salmon A, Nave R, Drollmann A. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir Med 2006;100:375–384.
7. Rohatagi S, Derendorf H, Zech K, Nave R, Banerji D. PK/PD of inhaled corticosteroids: the risk/benefit of inhaled ciclesonide. J Allergy Clin Immunol 2003;111:S380 (abstract 598).
8. Nave R, Fisher R, Zech K. In vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices. Biopharm Drug Dispos 2006;27:197–207.
9. Dietzel K, Engelstätter R, Keller A. Ciclesonide: an on-site activated steroid. Prog Respir Res 2001;31:91–93.
10. Mutch E, Nave R, McCracken N, Zech K, Williams F. The role of esterases in the metabolism of ciclesonide to desisobutyrylciclesonide in human tissue. Biochem Pharmacol 2007;73:1657–1664.
11. Nave R, Meyer W, Fuhst R, Zech K. Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide. Pulm Pharmacol Ther 2005;18:390–396.