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

Abstract

Aims: Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti-inflammatory response and side-effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat-dose inhalation.

Methods: This pharmacokinetic substudy was part of a previously published open-label, randomised, placebo-controlled, 7-period crossover study to evaluate the short-term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 microg twice daily) and FP (375, 750, 1000 microg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high-dose treatment period (BUD 1600 microg twice daily and FP 1000 microg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and 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 different elimination half-lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R-and 22S-epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP's higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung.

Conclusions: This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals 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 predicted 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.

Figure 1

a) Individual concentration data for BUD 22R-and 22S-epimers (solid line and dashed line, respectively) on the 5th day of 1600 µg twice daily via pMDI. The horizontal line represents the LOQ at 0.05 ng ml⁻¹. b) Individual concentration data for FP on the 5th day of 1000 µg twice daily via pMDI. The horizontal line represents the LOQ at 0.02 ng ml⁻¹. The peak concentrations obtained after BUD were greater than after FP.

Figure 2

Ratio of BUD 22R-to 22S-epimers vs time for each individual. A ratio of 1 : 2 and 2 : 1 would appear equidistant from the line of unity, as the data are shown on a logarithmic scale.

Figure 3

a) Individual concentration for BUD 22R-and 22S-epimers (solid line and dashed line, respectively) for all nine subjects. The bold line shows the biased fit of the mono-exponential absorption mono-exponential disposition model. b) Shows the less biased description of the data with two subjects removed. These two subjects require a two compartment disposition model to accurately characterize their pharmacokinetics, resulting in a more sustained budesonide concentration between 4 and 12 h postdose.

Figure 4

a) Individual concentration for FP for all nine subjects. The bold line shows the fit of the mono-exponential absorption mono-exponential disposition model. b) shows the fit of the pharmacokinetic model, which permitted a diurnal variation in the rate of elimination (a more rapid elimination half-life during the day).