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

Aims Pharmacokinetic variability is likely to be a significant factor contr ibuting to the interindividual differences in dose requirements anti-inflam matory response and side-effects with inhaled corticosteroids (ICS), but th ere is limited information about the disposition of ICS during regular dosi ng with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual vari ability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone pr opionate (FP) after repeat-dose inhalation. Methods This pharmacokinetic substudy was part of a previously published op en-label, randomised, placebo-controlled, 7-period crossover study to evalu ate the short-term effects on plasma cortisol levels of inhaled BUD (400, 8 00, 1600 mu g twice daily) and FP (375, 750, 1000 mu g twice daily) via pMD I in a group of healthy male volunteers. On the fifth day of each high-dose treatment period (BUD 1600 mu g twice daily and FP 1000 mu g twice daily), venous blood samples were collected in nine subjects Frier to the last dos e and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of pla sma drug concentrations to determine the pharmacokinetics of epimeric BUD a nd FP following inhalation. Non-compartmental analysis and a mixed effects model were used to characterize the disposition profiles. Results Both drugs had a rapid absorption half-life (BUD 10 min vs FP 11.3 min), but quite dint rent elimination half-lives (BUD 2.4 h vs FP 7.8 h). A lthough there were intraindividual differences in the handling of the 22R-a nd 22S-epimers of BUD, then were no consistent pharmacokinetic differences between the two enantiomers ill the group as a whole. Consistent with previ ous reports of FP's higher volume of distribution (V) and lower systemic bi oavailability (F), the V/F ratio was lower for BUD than FP (498 1 vs 8100 1 ). The parameter with the greatest interindividual variability for both BUD and FD was the rate of systemic absorption from the lung. Conclusions This is the first report describing the pharmacokinetics of epi meric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variab ility in the rate of absorption of both drugs from the lung; (2) in some in dividuals there was a long t(1/2,z), for BUD, resulting in higher and more sustained plasma drug levels in the 4-12 h postdose period than would be pr edicted from single-dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher-than-expected plasma drug concentrations in the morning compared with the evening.