Tissue Accumulation Kinetics of Ciclesonide‐active Metabolite and Budesonide in Mice

Abstract

Inhaled corticosteroids (ICS) are mainstay treatment of asthma and chronic obstructive pulmonary disease. However, highly lipophilic ICS accumulate in systemic tissues, which may lead to adverse systemic effects. The accumulation of a new, highly lipophilic ICS, ciclesonide and its active metabolite (des-CIC) has not yet been reported. Here, we have compared tissue accumulation of des-CIC and an ICS of a moderate lipophilicity, budesonide (BUD), after 14 days of once-daily treatment in mice. Single, three or 14 daily doses of [ H]-des-CIC or [3 H]-BUD were administered subcutaneously to male CD1 albino mice, which were killed at 4 hr, 24 hr or 5 days after the last dose. Distribution of tissue concentration of radioactivity was studied by quantitative whole-body autoradiography. Pattern of radioactivity distribution across most tissues was similar for both corticosteroids after a single as well as after repeated dosing. However, tissue concentration of radioactivity differed between des-CIC and BUD. After a single dose, concentrations of radioactivity for both corticosteroids were low for most tissues but increased over 14 days of daily dosing. The tissue radioactivity of des-CIC at 24 hr and 5 days after the 14th dose was 2-3 times higher than that of BUD in majority of tissues. Tissue accumulation, assessed as concentration of tissue radioactivity 5 days after the 14th versus 3rd dose, showed an average ratio of 5.2 for des-CIC and 2.7 for BUD (p < 0.0001). In conclusion, des-CIC accumulated significantly more than BUD. Systemic accumulation may lead to increased risk of adverse systemic side effects during longterm therapy.

Autoradiography techniques and quantification of drug distribution

“…Scientists at AstraZeneca and ActivBiotech used QWBA to compare tissue accumulation of the active metabolite of ciclesonide (des-CIC), which is being developed for pharmaceutical use and is highly lipophilic, and budesonide, which is moderately lipophilic (Märs et al 2013). Male albino mice were given 1, 3, or 14 daily subcutaneous doses of 3 H-des-CIC or 3 H-budesonide and then the distribution of radioactivity was examined by QWBA.…”

Tailoring of corticosteroids in COPD management

“…In both COPD and asthma, however, these drugs are infrequently prescribed in comparison to the more familiar ICS [51]. Concerns were raised last year that ciclesonide seems to be more lipophilic than budesonide in mice models, which theoretically could increase systemic adverse events [52]. For mometasone, however, there is a lot of safety data from asthma [53], justifying its use in a new combination product.…”

New techniques for studying airway drug pharmacokinetics for asthma therapeutics

“…Quantitative whole body autoradiography (QWBA) is required to study the systemic disposition of the drug candidate but rarely through lung dosing because of the complexity associated with inhaled tracer administration. Lung tissue can be resected and homogenized [2], or, in terms of autoradiography, punch samples from the cryo-preserved slices taken for subsequent chromatography and drug quantification [3]. Once efficacy and tolerability has been shown in selected animal systems, data needs to be generated on 'drugability', i.e.…”