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Risk-Benefit Value of Inhaled Corticosteroids*: A Pharmacokinetic/Pharmacodynamic Perspective FREE TO VIEW

Shashank Rohatagi, PhD, MBA; Hartmut Derendorf, PhD; Karl Zech, PhD
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*From Aventis Pharmaceuticals (Dr. Rohatagi), Bridgewater, NJ; Department of Pharmaceutics (Dr. Derendorf), University of Florida, Gainesville, FL; and Altana Pharmaceuticals (Dr. Zech), Konstanz, Germany.

Correspondence to: Shashank Rohatagi, PhD, MBA, Aventis Pharmaceuticals, Mail Stop: BWM-203F, Route 202–206, PO Box 6800, Bridgewater, NJ 08807-0800; e-mail: shashank.rohatagi@aventis.com

Chest. 2003;123(3_suppl):430S-431S. doi:10.1378/chest.123.3_suppl.430S-a
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Inhaled corticosteroids (ICS) induce therapeutic and adverse systemic effects mediated via the same receptor site. Analyzing pharmacokinetic/pharmacodynamic parameters of ICS helps quantify and obtain a risk-benefit value (RBV). Targeted efficacy with minimal adverse effects helps quantify an appropriate RBV. Lung deposition/targeting, receptor binding, volume of distribution, pulmonary retention, and lipid conjugation are a few of the important pharmacokinetic parameters to be considered when looking at the benefits of ICS. Oral bioavailability, particle size, and inactive drug at the oropharynx (for local side effects), plasma protein binding, rapid metabolism, high clearance, and lower systemic half-life are associated with low risks for adverse effects (Fig 1 ).

ICS potency is enhanced by solution inhalers that deliver higher pulmonary deposition (particle size < 2 μm in diameter), ensuring small airway targeting and minimal local adverse effects, while suspension inhalers deliver larger particles (3.5 to 4.0 μm) increasing local effects. After inhalation, the combination of the dose delivered to the lung (pulmonary availability) and GI tract (oral bioavailability) constitutes ICS systemic availability. Ideally, low oral bioavailability ensures a low incidence of systemic side effects.

Pharmacologically active ICS have therapeutic effect in tissue, creating a potential for local side effects in the throat and oral cavities. These local effects are minimized if inactive ICS are activated only in disease-specific lung tissue after inhalation with little intrinsic activity of the parent drug. As a portion of ICS reach the systemic circulation creating adverse effects, protein binding minimizes these because only unbound drug binds to receptor sites, allowing fewer adverse systemic effects while still remaining efficacious.

These properties, together with others, determine the efficacy and safety of ICS. Available agents, including budesonide and fluticasone, currently lack the complete set of parameters described to optimize RBV. Ciclesonide, a novel, potent ICS in development, demonstrates high efficacy in all asthma severities with negligible cortisol suppression. These remarkable improvements in RBV can possibly be explained by the pharmacokinetic/pharmacodynamic properties of ciclesonide.

Abbreviations: ICS = inhaled corticosteroids; RBV = risk-benefit value




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