Clinical Pharmacokinetics of Inhaled Budesonide

The corticosteroid budesonide is a 1: 1 racemic mixture of 2 epimers, (22R)-and (22S)-, and is available in 3 different inhaled formulations for the management of asthma: a pressurised metered dose inhaler (pMDI), a dry powder inhaler (DPI) and a solution for nebulised therapy. Inhaled corticosteroids such as budesonide reach the systemic circulation either by direct absorption through the lungs (a route that is much more important than previously recognised) or via gastrointestinal absorption of drug that is inadvertently swallowed. Although the pharmacokinetics of budesonide have been extensively investigated following oral and intravenous administration, relatively few studies have defined the systemic disposition of budesonide after inhalation.

Drug deposition in the lungs depends on the inhaler device: 15% of the metered dose of budesonide reached the lung with a pMDI compared with 32% with a breath-actuated DPI. In patients with asthma (n = 38) receiving different doses of budesonide by DPI (Turbuhaler®), the pharmacokinetic parameters peak plasma concentration (C_max) and area under the concentration-time curve (AUC) were dose-dependent after both single dose and repeat dose (3 weeks) administration; time to C_max (t_max) was short (0.28 to 0.40 hours) and the elimination half-life approximately 3 hours. Both AUC and C_max were linearly related to budesonide dose. In a small group of healthy male volunteers (n = 9), the pharmacokinetics of budesonide 1600μg twice daily via pMDI were assessed on the fifth day of administration. Mean model-independent parameters for (22R)-budesonide were as follows: C_max 1.8 μg/L, t_max0.46 hours, elimination half-life 2.3 hours and oral clearance 163 L/h, and there were no enantiomer-specific differences in drug disposition.

Budesonide undergoes fatty acid conjugation within the lung, but very limited pharmacokinetic data are available to define the pulmonary absorption characteristics. There is evidence from a population analysis that the pulmonary absorption of budesonide is prolonged and shows wide interindividual variation. Further pharmacokinetic studies are required to define the time-course of budesonide absorption through the lung in specific patient groups, and to investigate the effect of new inhaler devices (especially chlorofluorocarbon-free pMDIs) on the pharmacokinetic profile and systemic drug exposure.