Establishing bioequivalence for orally inhaled drug products

We thank Dr García Arieta for his interest and comments on our article.

The use of in vitro data alone is a feature of the European guidance [1]. Dr García Arieta's comment that this route of approval is unlikely to be a common occurrence appears to be in-line with our conclusion that unless there is a high degree of pharmaceutical equivalence between the test and reference products, consideration of a combination of preclinical and clinical data may be preferable to abridged approaches relying on in vitro data alone.

We did not address the bioequivalence of systemically acting drugs but mentioned it to contrast the simplicity compared to inhaled drugs [2]. Dr García Arieta wrote that in vitro differences may be considered clinically irrelevant, but that is usually in the context of some understanding of the in vivo–in vitro correlation. However, such a correlation for inhaled drugs is generally lacking.

Dr García Arieta did not agree with our conclusions on the value of pharmacokinetic data for some of the bioequivalence examples we cited [2] but rather advocates pharmacokinetic data for its superior sensitivity. Although pharmacokinetic data may well be sensitive, for example, to a change in the particle size profile, dissolution rate or altered regional lung deposition, these parameters may not exhibit the same relevance for efficacy. There are few well-documented examples with robust data for in vitro profiling, pharmacokinetics, lung deposition and clinical efficacy testing and, therefore, insufficient data to allow a general conclusion at this time.

The assumption that systemic pharmacokinetic data are a valid surrogate of topical efficacy in the lung has been questioned [2,3]. Dr García Arieta suggests this is a misinterpretation of the supporting data we cited [4], arguing that it is simply a matter of tissue distribution and that after oral administration fluticasone propionate distributes to fatty tissues and not to the lungs. The volume of distribution of fluticasone propionate, and indeed of any drug, is a primary pharmacokinetic parameter and independent of its route of administration [5]. Therefore at steady-state, fluticasone propionate's volume of distribution and its rate and extent of tissue partitioning should be the same for oral and inhaled administration. After single dose administration the rate of tissue distribution may well be relevant, but in the cited study [4], 6 weeks dosing was used and steady-state equilibrium should have been achieved between plasma and tissues compartments. However, despite the higher systemic concentration of fluticasone propionate achieved after oral compared to inhaled dosing, only the inhaled regimens were efficacious, suggesting a lack of equilibrium between the site of action in the lung and the drug concentrations in plasma.

Declaration of interest

Both authors are employees of GlaxoSmithKline, who develop and manufacture inhaled drug products.