Asthma Knowledge Centre
Alvesco
Pharmacokinetics of Alvesco
An innovative inhaled corticosteroid
During the last two decades, several ICS have been developed with a focus on improving the therapeutic index of ICS.1 However, none possess all of the properties that would make them ‘ideal’;2 unwanted deposition and activity of the drug at non-pulmonary sites remains problematic and increases the potential for local and systemic adverse events.
An ‘ideal’ ICS for the treatment of asthma should have:2-4
- High local activity in the lung
- Targeted activation in the lungs
- Low oral bioavailability
- A long residence time in the lung
- High protein binding and high systemic clearance
- Minimal systemic adverse events
The clinical efficacy and systemic activity of an ICS are influenced by its pharmacology.2 Alvesco exhibits high pulmonary deposition, targeted activation, very high plasma protein binding, rapid metabolism and extensive clearance.2 Combined, these properties contribute to an enhanced safety profile, while maintaining efficacy comparable with or better than other available ICS (see Clinical efficacy, Safety and Tolerability sections). The cellular pathways of Alvesco are shown in Figure 1.5
Figure 1. The cellular pathways of Alvesco
GCS=glucorticosteroid; des–CIC=desisobutyryl ciclesonide. Reprinted from 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; 18:390-6. With permission from Nycomed.
The pharmacologic properties of Alvesco provide increased benefits in comparison to other currently available ICS (Table 1):
- Alvesco is an inactive parent compound
- Activation occurs primarily in the airways
- The active metabolite of Alvesco, desisobutyryl-ciclesonide (des-CIC), has a high glucocorticoid –receptor affinity
- Alvesco has low oropharyngeal deposition and activation and, therefore, a low potential for oropharyngeal adverse events
- Alvesco exhibits high pulmonary deposition
- Alvesco has the anti-inflammatory activity characteristic of a potent corticosteroid
- Des-CIC is highly lipophilic and forms lipid conjugates in the lung, which may prolong its antiinflammatory effect and allow for once-daily dosing
- Alvesco has low oral bioavailability (<1%)
- Alvesco is highly protein bound (~99%) in the systemic circulation, limiting its ability to interact with glucocorticoid receptors outside of the lung
- Alvesco demonstrates high systemic clearance
| Parameter | Beclomethasone dipropionate/17- beclomethasone monopropionate | Budesonide | Fluticasone propionate | Mometasone furoate | Alvesco/ desisobutyryl- ciclesonide | Significance |
|---|---|---|---|---|---|---|
| Available delivery devices |
HFA–MDI | HFA–MDI DPI (Turbuhaler®) |
HFA–MDI DPI (Diskus®/ Accuhaler®) |
DPI (Twisthaler®) | HFA–MDI | HFA–MDI can increase pulmonary deposition and penetration into the peripheral airway |
| Oral bioavailability |
<1%(P)*† 26%(A)*†8 |
11%**9 | <1%**10 | <1%¶11 | <1%(P)** <1%(A)**12 |
Reduced systemic availability and low potential for associated adverse events |
| Pulmonary deposition |
53%‡13 | 18–28%¶14 | 29%‡15 | 13.9%‡16 | 52%‡17, 18 | Increases local anti-inflammatory action and can reduce dose required |
| Formulation | Solution19 | Data currently unavailable for budesonide via HFA–MDI |
Suspension for HFA–MDI20 |
Dry powder (with lactose)21 |
Solution17 | A solution contributes to greater lung deposition through generation of a greater proportion of ultrafine particles |
| Targeted activation |
Yes8 | No22 | No22 | No | Yes23, 24 | Activation to a potent antiinflammatory glucocorticoid occurs rapidly in the lung, not in the mouth or oropharynx |
| Glucocorticoid – receptor binding affinity |
53(P) 1345(A)25 |
93525 | 180025 | 230015 | 12(P) 1212(A)26 |
Potent antiinflammatory action |
| Esterification | No27 | Yes27 | No27 | Unknown | Yes23, 28 | Lung tissue acts as a storage depot for drug, prolonging anti-inflammatory effects and allowing for once-daily dosing |
| Lipophilicity | Low(P)/High(A)29 | Low29 | High29 | Very high29 | Very high(P) Very high(A)23, 24 |
Associated with greater tissue retention, allowing for once-daily dosing |
| Protein binding: free fraction ratio (%) |
87%:13%(P)15 | 88%:12%9 | 90–98%: 2–10%15, 30 |
98–99%:~1%11 | 99%:1%(P) 99%:1%(A)31 |
Reduced concentration of active ICS available systemically to cause adverse events |
| T1/2 (hr) |
0.5(P)§ 2.7(A)§8 |
2.8§9 | 5.6–6.1§32 | 4.5§33 | 0.38(P)§ 3.5(A)§12 |
Decreased potential for systemic adverse events |
| Vd (L) | 20(P)§ 424(A)§8 |
183–30115 | 253–28232 | 332§33 | 207(P)§ 897(A)§15 |
Extensively distributed and bound in tissue |
| CL (L/hr) | 150(P)§ 120(A)§8 |
84§9 | 80–93§32 | 53.5§11 | 152(P)§ 228(A)§15 |
Decreased potential for systemic adverse events |
*Following inhaled administration; †Established with chlorofluorocarbon–MDI formulation; ‡Established with HFA–MDI formulation; §Following intravenous administration; ¶Established with DPI; **Following oral administration HFA–MDI=hydrofluoroalkane metered dose inhaler; DPI=dry powder inhaler; (P)=parent compound; (A)=active metabolite; ICS=inhaled corticosteroid; T1/2 =half-life; Vd=volume of distribution; CL=clearance.
Alvesco, a parent compound
Alvesco (the R-epimer of ciclesonide: C32H44O7; molecular weight: 540.7) is an inactive corticosteroid parent compound that has minimal pharmacologic activity.7 Conversion of Alvesco occurs in the airway epithelium where enzymatic cleavage of R-ciclesonide by endogenous esterases releases the active primary metabolite, des-CIC.6,7
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. 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.
3. Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ. Inhaled corticosteroids: past lessons and future issues. J Allergy Clin Immunol 2003;112:S1–S40.
4. Rohatagi S, Appajosyula S, Derendorf H, Szefler S, Nave R, Zech K, et al. Risk-benefit value of inhaled glucocorticoids: a pharmacokinetic/pharmacodynamic perspective. J Clin Pharmacol 2004;44:37–47.
5. 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.
6. Dietzel K, Engelstätter R, Keller A. Ciclesonide: an on-site activated steroid. Prog Respir Res 2001;31:91–93.
7. Stoeck M, Riedel R, Hochhaus G, Hafner D, Masso JM, Schmidt B, et al. In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide. J Pharmacol Exp Ther 2004;309:249–258.
8. Daley-Yates PT, Price AC, Sisson JR, Pereira A, Dallow N. Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol 2001;51:400–409.
9. Ryrfeldt A, Andersson P, Edsbacker S, Tonnesson M, Davies D, Pauwels R. Pharmacokinetics and metabolism of budesonide,
a selective glucocorticoid. Eur J Respir Dis Suppl 1982;122:86–95.
10. Falcoz C, Oliver R, McDowall JE, Ventresca P, Bye A, Daley-Yates PT. Bioavailability of orally administered micronised fluticasone propionate. Clin Pharmacokinet 2000;39 Suppl 1:9–15.
11. Sharpe M, Jarvis B. Inhaled mometasone furoate: a review of its use in adults and adolescents with persistent asthma. Drugs 2001;61:1325–1350.
12. Nave R, Bethke T, Marle SV, Zech K. Pharmacokinetics of [14C] ciclesonide after oral and intravenous administration to
healthy subjects. Clin Pharmacokinet 2004;43:479–486.
13. 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.
14. Pitcairn G, Reader S, Pavia D, Newman S. Deposition of corticosteroid aerosol in the human lung by Respimat Soft Mist inhaler compared to deposition by metered dose inhaler or by Turbuhaler dry powder inhaler. J Aerosol Med 2005;18:264–272.
15. Winkler J, Hochhaus G, Derendorf H. How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc 2004;1:356–363.
16. Pickering H, Pitcairn GR, Hirst PH, Bacon PR, Newman SP, Affrime MB, et al. Regional lung deposition of a technetium 99m-labeled formulation of mometasone furoate administered by hydrofluoroalkane 227 metered-dose inhaler. Clin Ther 2000;22:1483–1493.
17. 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.
18. 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.
19. Micheletto C, Guerriero M, Tognella S, Dal Negro RW. Effects of HFA- and CFC-beclomethasone dipropionate on the bronchill response to methacholine (MCh) in mild asthma. Respir Med 2005;99:850–855.
20. Flovent HFA. http://www.gw-flovent.com/.
21. ASMANEX TWISTHALER product information. http://www.spfiles.com/piasmanex.pdf.
22. Dendorf H, Hochhaus G, Meibohm B, Mollmann H, Barth J. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids. J Allergy Clin Immunol 1998;101:S440–SS446.
23. 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.
24. Stoeck M, Riedel R, Hochhaus G, Hafner D, Masso JM, Schmidt B, et al. In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide. J Pharmacol Exp Ther 2004;309:249–258.
25. Wuerthwein G, Rehder S, Rohdewald P. Lipophilicity and receptor affinity of glucocorticoids. Pharmazeutische Zeitung issenschaft 1992;137:161–167.
26. Weinbrenner A, Huneke D, Zschiesche M, Engel G, Timmer W, Steinijans VW, et al. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab 2002;87:2160–2163.
27. Miller-Larsson A, Mattsson H, Hjertberg E, Dahlback M, Tunek A, Brattsand R. Reversible fatty acid conjugation of budesonide. ovel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998;26:623–630.
28. 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.
29. Issar M, Sahasranaman S, Buchwald P, Hochhaus G. Differences in the glucocorticoid to progesterone receptor selectivity of Inhaled glucocorticoids. Eur Respir J 2006;27:511–516.
30. Taylor S, Harker A. Modification of the ultrafiltration technique to overcome solubility and non-specific binding challenges associated with the measurement of plasma protein binding of corticosteroids. J Pharm Biomed Anal 2006;41:299–303.
31. Rohatagi S, Luo Y, Shen L, Guo Z, Schemm C, Huang Y, et al. Protein binding and its potential for eliciting minimal systemic ide effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther 2005;12:201–209.
32. Brutsche MH, Brutsche IC, Munawar M, Langley SJ, Masterson CM, Daley-Yates PT, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000;356:556–561.
33. Affrime MB, Cuss F, Padhi D, Wirth M, Pai S, Clement RP, et al. Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers. J Clin Pharmacol 2000;40:1227–1236.