Allometric Modeling of Ciclesonide, a Nonhalogenated Glucocorticoid, and Its Active Metabolite, Desisobutyrylciclesonide, Using Animal-Derived Pharmacokinetic Parameters Nuggehally R. Srinivas, PhD, FCP, Preeti Ahlawat, MS, 1 and Jafar Bhasha Shaik, MPharm 2 Ciclesonide, a novel glucocorticosteroid, through a rapid metabolism to desisobutyryl-ciclesonide (des-ciclesonide), provides an effective treatment option for asthma episodes by the inhaled route of administration. The availability of pharmacokinetic parameters (clearance [CL/F]; volume of distribution [V d /F]; elimination half-life [T 1/2 ]; and elimination rate constant [K el ]) in mice, rats, rabbits, and dogs enabled the prediction of human parameter values for des-ciclesonide using the well-accepted tool of allometry after intravenous administration of ciclesonide. However, as a result of the rapid conversion of ciclesonide, it was possible to perform allometry for the CL parameter only. Simple allometry (CL = 4.781W 0.7874 ; R 2 = 0.9968) appeared to predict the CL of ciclesonide in close proximity of the observed value (observed: 101.25 L/h versus predicted: 135.62 L/h). In a similar manner, simple allometry predicted the human pharmacokinetic parameters of des- ciclesonide (CL/F, V d /F, T 1/2 , and K el ) within a two- to threefold range of the observed values. The allometric equations for des-ciclesonide parameter values were: CL/F = 4.8166W 0.492 (R 2 = 0.8598); V d /F = 19.052W 0.632 (R 2 = 0.9049); T 1/2 = 3.7598W 20.1611 (R 2 = 0.8551); and K el = 0.1832W 0.1596 (R 2 = 0.8632). In conclusion, the data suggested that allometry tool may be amenable for the prediction of the pharmacokinetic parameters of des-ciclesonide despite differences in the conversion rates and bioavailability of the active metabolite in various animal species. Keywords: allometry, ciclesonide, des-ciclesonide, clearance, volume distribution and asthma, glucocorticoid INTRODCUTION Ciclesonide provides novel and effective glucocorti- coid intervention through the inhalation route and is recommended for the treatment of recurrent asthmatic episodes. 1–3 Interestingly, ciclesonide by itself has negligible activity; however, its metabolite, desisobutyryl-ciclesonide (des-ciclosenide), which is rapidly formed in vivo, displays a very high affinity for glucocorticoid receptors. 4,5 As a result of extensive first-pass metabolism, both the levels of ciclesonide and des-ciclesonide tend to be extremely low as documented in both human and animal radiolabeled studies of ciclesonide. 4,5 Hence, a small fraction of the drug that escapes the inhaled route and gets into the gastrointestinal tract is less likely to contribute to systemic exposure of either the parent drug and/or its active metabolite. The pharmacokinetics of ciclesonide and des- ciclesonide have been studied in animal species such as mice, rats, rabbits, and dogs after both oral and intravenous administration of ciclesonide. 6 From Integrated Drug Development, Suramus Biopharm, J. P. Nagar I Phase, Bangalore, India., 1 Current affiliation: ClinTec International (India) Pvt. Ltd., Koramangala, Bangalore, India., 2 Current affiliation: University of Pittsburgh, Pittsburgh, PA. The authors declare no conflicts of interest. Address correspondence and reprint requests to Nuggehally R. Srinivas, Chief Scientific Officer, Suramus Biopharm, 77, 10th cross, 29th main, J. P. Nagar I Phase, Bangalore 560 078, India. American Journal of Therapeutics 20, 261–266 (2013) 1075–2765 Ó 2013 Lippincott Williams & Wilkins www.americantherapeutics.com