Systemic bioavailability of fluticasone proprionate

We read the recent article of Daley-Yates & Baker [1] regarding the systemic bioavailability of four consecutive 800 µg doses intranasal fluticasone aqueous spray given over 24 h in healthy volunteers. The pharmacokinetic data presented suggest a low degree of systemic exposure in terms of the plasma fluticasone concentration as compared with historical data from a reference intravenous dose. They also postulate in the discussion that the systemic bioavailability of fluticasone is much lower than other intranasal aqueous corticosteroid formulations such as budesonide or triamcinolone acetonide when given via the intranasal route, because of differences in their oral bioavailability.

The lower plasma concentrations of fluticasone as compared with budesonide or triamcinolone are more likely to be due to differences in lipophilicity and volume of distribution, in that highly lipophilic drugs such as fluticasone preferentially distribute into the systemic fat tissue reservoir, resulting in a large volume of distribution and a relatively lower concentration in the water soluble blood compartment at steady-state [2]. Consequently, measuring only the low concentration of fluticasone in the plasma compartment will greatly underestimate the total systemic exposure, and this is borne out by several studies which have evaluated systemic adverse effects of intranasal fluticasone given at much lower daily doses than were evaluated by Daley-Yates & Baker.

In a study of healthy volunteers significant HPA-axis suppression was shown in terms of a 43% reduction of overnight urinary cortisol excretion with intranasal fluticasone spray 200 µg daily compared with placebo, whereas the effect of triamcinolone spray 220 µg daily was not significant (23% reduction) [3]. In another study in patients with allergic rhinitis, intranasal triamcinolone spray 220 µg daily or budesonide spray 200 µg daily exhibited no significant effects on 24 h or fractionated cortisol profiles measured in blood or urine [4]. Furthermore in healthy volunteers receiving intranasal fluticasone spray 200 µg daily for 1 week followed by 400 µg daily for a second week, there was a 37% fall in 08 00 h serum cortisol, a 24% fall in 24 h urinary cortisol, a 45% fall in serum osteocalcin as well as a 28% fall in peripheral blood lymphocytes glucocorticoid receptor mRNA expression, all of which were highly significant effects (P < 0.001) [5]. Moreover after stopping fluticasone for one week there was persistent suppression of peripheral lymphocyte glucocorticoid receptor mRNA expression (33% reduction) which would suggest prolonged systemic retention of fluticasone with sustained release from the systemic tissue reservoir into the blood compartment. This would be consistent with its large volume of distribution due to its lipophilicity, with much higher tissue than plasma concentrations. In the same study [5], twice the daily dosage of intranasal budesonide was found to exhibit significant effects of comparable magnitude on the same systemic bioactivity markers, although there was no persistent suppression of mRNA after one week of washout. In patients with allergic rhinitis intranasal fluticasone spray 200 µg daily produced a 38% fall in peripheral blood eosinophil count and a 13% fall in 24 h urinary cortisol excretion, although only the former achieved statistical significance [6]. An apparent lack of HPA-axis suppression with 800 µg daily of intranasal fluticasone spray [7] using a 250 µg ACTH stimulation test may be explained by the known insensitivity of this test, as 250 µg represents a supraphysiological dose of ACTH, with much lower doses of ACTH (i.e. 0.5–1.0 µg) being as effective in producing a stimulated cortisol reponse [8].

It is therefore more clinically relevant to evaluate sensitive tests of potential systemic bioactivity in order to assess the true systemic exposure of intranasal fluticasone, rather than measuring the systemic bioavailability in terms of its plasma concentration. Indeed, it is the presence or absence of systemic adverse effects which matters more to the prescribing clinician, in terms of evaluating the benefit/risk ratio of intranasal corticosteroid formulations.