Pharmacokinetics of epimeric budesonide and fluticasone propionate after repeat dose inhalation – intersubject variability in systemic absorption from the lung

摘要: Aims Pharmacokinetic variability is likely to be a significant factor contributing the interindividual differences in dose requirements, anti-inflammatory response and side-effects with inhaled corticosteroids (ICS), but there limited information about disposition of ICS during regular dosing pressurized metered inhaler (pMDI). This study uses mixed effects modelling approach quantify compare pharmacokinetics epimeric budesonide (BUD) fluticasone propionate (FP) after repeat-dose inhalation. Methods pharmacokinetic substudy was part previously published open-label, randomised, placebo-controlled, 7-period crossover evaluate short-term on plasma cortisol levels BUD (400, 800, 1600 µg twice daily) FP (375, 750, 1000 µg via pMDI group healthy male volunteers. On fifth day each high-dose treatment period (BUD daily daily), venous blood samples were collected nine subjects prior last at 15 min, 30 min, 1, 2, 4, 6 8 h postdose for measurement drug concentrations determine following inhalation. Non-compartmental analysis model used characterize profiles. Results Both drugs had rapid absorption half-life 10 min vs 11.3 min), quite different elimination half-lives 2.4 h 7.8 h). Although intraindividual handling 22R-and 22S-epimers BUD, no consistent between two enantiomers as whole. Consistent previous reports FP’s higher volume distribution (V) lower systemic bioavailability (F), V/F ratio than (498 l 8100 l). The parameter greatest both rate from lung. Conclusions first report describing repeat inhalation pMDI. Three observations may clinical relevance: (1) considerable intersubject lung; (2) some individuals long t½,z resulting more sustained 4–12 h would predicted single-dose data; (3) evidence diurnal variation pharmacokinetics, higher-than-expected morning compared evening.