The Effect of Protein Binding on Adrenal Suppression Potential of Inhaled Corticosteroids

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RATIONALE: High protein-binding levels associated with some inhaled corticosteroids (ICS) may predict low levels of cortisol suppression. METHODS: An integrated pharmacokinetic/pharmacodynamic model based on the circadian rhythm of cortisol secretion was developed to accurately predict ICS-related cortisol suppression (% decrease in 24h cortisol area under the curve) using individual pharmacokinetic profiles and relative receptor binding affinities. The model was applied to several ciclesonide, fluticasone propionate and budesonide studies. Model-predicted cumulative cortisol suppressions (p) were compared with experimentally measured values (m). RESULTS: Accurate predictions were obtained for ciclesonide (metered-dose inhaler [MDI]; protein binding of the active metabolite desisobutyryl-ciclesonide=98.3%) 320μg twice daily (ex-actuator; bid; 4.9%p, 6.5%m), 640μg once daily (qd) at 7AM (6.5%p, 6.5%m) and 640μg qd at 7PM (2.9%p, 1.9%m). Predictions for budesonide (Turbuhaler®; protein binding=88%) also compared well with study observations: 400 μg bid (19.3%p, 19%m) and 1000μg bid (33.5%p, 36%m). Assuming a 90% protein binding (p90) for fluticasone propionate, the model slightly overpredicted measured values. However, the model greatly underpredicted cortisol suppression utilizing a recently reported 99.3% (p99.3) protein binding. Predictions for fluticasone propionate (p90 and p99.3, respectively) were 20.5%p and 1.9%p for 200 μg bid (Diskus®), 38.1%p and 4.5%p for 500 μg bid (Diskus®) and 62.2%p and 11.7%p for 880μg bid (pressurized MDI) compared with measured values of 14%m, 27%m and 59%m, respectively. CONCLUSIONS: ICS protein binding levels appear to correlate well with degrees of cortisol suppression. The recently reported high protein binding of fluticasone propionate is not consistent with the predicted and observed degree of cortisol suppression.