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Ciclesonide: A Pro-Soft Drug Approach for Mitigation of Side Effects of Inhaled Corticosteroids

https://doi.org/10.1016/j.xphs.2016.05.004Get rights and content

Abstract

Inhaled corticosteroids are used as one of the first-line drug therapy in patients with asthma. However, their long-term use is associated with various oropharyngeal and systemic side and adverse effects. Design of pro-soft drug is one of the strategies, which was adopted in the design of ciclesonide for mitigation of side effects usually observed with the use of inhaled corticosteroids. Ciclesonide, a pro-soft drug, is converted to an active metabolite desisobutyryl-ciclesonide in the lungs. The anti-inflammatory effect of desisobutyryl-ciclesonide is much higher than ciclesonide, and therefore, the local effect of the metabolite is higher with lower systemic side effects. Ciclesonide has favorable pharmacokinetic and pharmacodynamic properties as inhaled corticosteroid including low oral bioavailability, high plasma protein binding and rapid systemic clearance, high pulmonary deposition and distribution and long pulmonary residence duration. These advantageous properties make ciclesonide a very effective treatment option with low side effects. Various clinical studies support safety and efficacy of ciclesonide use in mild, moderate, and severe asthma patients.

Introduction

Asthma is an inflammatory disorder which is characterized by airways obstructions and hyper responsiveness in the lungs.1 This inflammatory disorder affects more than 350 million people worldwide including 30 million people in United States and more than 4000 deaths per year are reported worldwide on account of asthma.2

Major treatment options focus on the better management of the lung inflammation so that patients could lead a normal life with minimal side and adverse effects. Most of the international asthma control guidelines suggest the use of inhaled corticosteroids (ICSs) as a first line of treatment; however, severe asthma patients may require taking oral corticosteroids as well.3 ICS treatment targets local deposition of corticosteroids in the pulmonary tissues with minimal systemic concentrations and minimal side and adverse effects. Use of ICS is found to relieve major asthma symptoms including inflammation, hyper responsiveness, and exacerbations.1, 4 It also helps to improve pulmonary functions and the quality of life in asthma patients. Seven ICSs are available in the market including budesonide, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate, ciclesonide, and mometasone furoate, and so forth.

ICSs are used as one of the first line of drug therapy in patients with asthma. ICSs have been very successful in controlling asthma symptoms but the toxicity associated with their long-term use is a concern.5 Ciclesonide, an ICS, was designed as a pro-soft drug to mitigate the side effects.4, 6 By virtue of structural design with predictable and controlled metabolism, it possesses favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this review, we discuss the PK and PD properties of ciclesonide and review the results of clinical efficacy and safety studies.

Section snippets

Soft Drug Approach

The concept of soft drug was introduced in 1976 by N. Bodor in an attempt to design safe drugs with less undesirable side effects. Soft drugs are isosteric and isoelectronic analogue of lead molecules, which undergoes controlled and predictable metabolism after exerting necessary therapeutic action.7 Most undesirable side effects result from nonspecific and off-target binding of parent molecule and generation of active metabolites responsible for these undesirable side effects. In many cases,

Fate of Inhaled Corticosteroids

ICSs are anti-inflammatory agents, widely used as first line of treatment in patients with asthma.4, 9 Seven ICSs are available in the market including budesonide, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate, ciclesonide, and mometasone furoate. These ICSs vary in their chemical structure and physicochemical properties and exhibit different PK and PD properties as explained in Table 1.4, 10, 11, 12, 13, 14, 15, 16 To better understand the safety and efficacy of

Systemic and Oropharyngeal Side Effects of Inhaled Corticosteroids

Generally, ICSs are used for longer duration in patients with asthma and their long-term use leads to number of systemic side effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression, statural growth reduction in children, decrease in bone density, and ocular side effects.5, 19 HPA axis regulates the cortisol secretion in the body in response to mental as well as physical stress and operates in a negative feedback controlled system.20 Presence of ICS in the blood may cause

Ciclesonide—A Pro-Soft Drug: Pharmacokinetics and Pharmacodynamics

Ciclesonide is a novel pro-soft drug ICS, which gets activated to its active drug, called desisobutyryl-ciclesonide (des-CIC) by pulmonary esterases in the lungs, exert its therapeutic actions in the lungs and gets inactivated in a controlled metabolism.4, 14 It possesses several PK and PD properties which leads to an advantageous safety profile and fewer oropharyngeal and systemic side effects in comparison to existing ICSs such as beclomethasone dipropionate and fluticasone propionate.27, 28

Initial Efficacy Studies During Ciclesonide Development

A number of preclinical and clinical studies conducted in the initial years of ciclesonide development showed efficacy of ciclesonide in comparison to other ICSs. Bundschuh et al.54 evaluated ciclesonide in an animal model of inflammation and showed that ciclesonide is equipotent to budesonide in reducing the inflammation and is associated with significant reduction in thymus and adrenal involution (measures of systemic side effects55) in comparison to budesonide. Ciclesonide exhibited similar

Recent Clinical Safety and Efficacy Studies of Ciclesonide

Recent efficacy and safety studies support that ciclesonide is effective to improve the lung functions with very low oropharyngeal and systemic side effects in comparison to other ICSs. A 160-μg QD dose of ciclesonide demonstrated similar efficacy to 400-μg QD of budesonide (400 μg daily) in patients with persistent asthma.27 Administration of ciclesonide from 100 to 800 μg once daily demonstrated efficacy in patients with asthma with improvement in the PEF and forced expiratory volume.60

Safety and Efficacy Studies in Children With Asthma

ICS use is a major concern in children with asthma because ICS modify the linear growth especially lower leg growth rates in children when used. However, clinical studies using ciclesonide as ICS in children with asthma suggest that ciclesonide administration does not significantly affect the linear growth as a systemic side effect in children.9, 65 Agertoft et al.66, 67 suggest that once daily treatment of ciclesonide (320 μg) in children with asthma (6-12 years) has no significant effect on

Conclusion

Significant progress has been made with ICSs use in asthma treatment. Ciclesonide, a pro-soft drug and a novel ICS, has favorable pharmacokinetic and pharmacodynamic properties which lead to its advantageous safety and efficacy profile as assessed in various clinical studies.

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    Conflicts of interest: Jatinder Kaur Mukker and Hartmut Derendorf do not have any conflicts of interest. Ravi Shankar Prasad Singh is an AbbVie employee and may hold its stock and options.

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