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Side Effects With Inhaled Corticosteroids: Asthma Clinical Research

Published in Asthma

Side Effects With Inhaled Corticosteroids: Asthma Clinical ResearchModern delivery systems, such as HFA-based pMDI inhalers, enhance drug targeting to the lungs. Thus, lower ICS doses can be used, such that the clinical response is maintained but systemic exposure reduced. For example, conversion from CFC to HFA as a propellant moved the dose-response curve for drugs delivered using the HFA device toward the left, so lower doses are required to achieve the same therapeutic effect.> Conversely, a 1:1 substitution of the CFC to the more recent HFA formulations may result in greater systemic exposure and a higher potential for side effects.> Therefore, recommended doses of HFA devices are lower than older CFC-containing formulations. Large-volume spacers have also been recommended as a means of improving lung deposition, allowing dose reduction and minimization of ICS systemic bioavailability in adults and children. this

The Asthma Clinical Research Network conducted a randomized study to investigate the systemic bioavailability of different ICS and devices using overnight urinary cortisol suppression to assess dose response. The study took place over 6 weeks, with the first week consisting of a placebo run-in phase. Five ICS compounds were evaluated: FP (as a CFC-pMDI formulation and a DPI formulation); BUD (DPI formulation); BDP (CFC-pMDI formulation); FLU (CFC-pMDI formulation); and TAA (CFC-pMDI formulation). The results were used to relate the ICS dose and delivery mechanism to an estimated effect on cortisol suppression (ie, their systemic availability) and determine equisuppressive doses. Table 1 shows the estimated doses of the different formulations that would cause a 10% suppression of endogenous cortisol production. This study showed that FP delivered using a CFC-pMDI with a spacer required the lowest labeled dose to suppress cortisol production by 10%; and FLU, also delivered using a CFC-pMDI plus spacer, required the highest dose to obtain the same effect (Table 1). This study also showed that it is possible to conduct pharmacokinetic studies that allow comparison of hypothalamic-pituitary-adrenal axis suppression between different drug/device combinations. Such studies provide information regarding the potential for different ICS compounds, doses and formulations to cause systemic side effects.

Table 1—Estimated Doses of ICS Formulations That Would Produce a 10% Suppression in Cortisol

Formulation Labeled Dose, ^g (95% CI) Emitted Dose, ^g (95% CI)
FLU CFC-pMDI plus spacer 936 (484-1,387) 295 (153-437)
TAA CFC-pMDI plus spacer 787(627-947) 309 (246-371)
BDP CFC-pMDI plus spacer 548(230-866) 168(71-266)
FP DPI 445(0-918) 440 (0-907)
BUD DPI 268(153-383) 164 (94-235)
FP CFC-pMDI plus spacer 111(67-154) 68(41-95)