Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease

Abstract

AimsWe have previously shown that the systemic exposure to inhaled fluticasone propionate (FP) is reduced in asthmatics compared with healthy subjects. We have now compared its pharmacokinetics in patients suffering from chronic obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects ( n = 13). Methods A double-blind, randomized, cross-over study design was used. Plasma FP and serum cortisol were measured for 12 h after subjects received hydrofluoroalkane FP 1000 m g day -1 inhaled (via an MDI and spacer) for 7 days and following a single 1000-m g intravenous dose.Results The pharmacokinetics differed in the two groups. After inhalation, geometric least square means were significantly lower in the COPD group for the plasma AUC (1961 vs 2996 pg ml -1 h -1 for COPD and controls, respectively; P = 0.03) and the C max (235 vs 421 pg ml -1 for COPD and controls, respectively; P = 0.03). Suppression of serum cortisol concentration over 12 h was greater in healthy controls. Weighted mean serum cortisol concentration (nmol l -1 ) in healthy subjects and COPD was 93 and 170, respectively ( P = 0.03). The intravenous pharmacokinetic parameters for FP were comparable in the two groups, resulting in similar suppression of serum cortisol. Conclusions We conclude that the altered pharmacokinetics of inhaled fluticasone propionate in COPD caused less hypothalamic-pituitary-adrenal suppression than in healthy controls. This is further evidence that the systemic effects of inhaled corticosteroids should be assessed in patients and not healthy subjects.

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

“…Patient-specific factors such as age (29,30), height (30), and sex (31) have also been demonstrated to influence particle deposition patterns and/or the PK after drug inhalation. Airway diseases (e.g., asthma bronchiale or COPD) and even different disease stages altered the particle deposition patterns (32): The total bioavailability of fluticasone propionate (33)(34)(35) was decreased in patients with more severe asthma bronchiale and COPD. Similarly, maximum plasma concentrations and the exposure were decreased for inhaled fluticasone propionate and budesonide after provoking bronchoconstriction (decreased forced expiratory volume in 1 s (FEV1)) in asthma patients (36).…”

Biotransformation of Fluticasone: In Vitro Characterization

“…As recently shown by Singh et al (2003), the mean (range) systemic availability of a single 1000-g inhaled dose of FTP was 21.2% (14.3-31.4%) and 13.3% (8.5-20.9%) in healthy controls and adults with chronic obstructive pulmonary disease, respectively. Thus, when a therapeutic dose of FTP is delivered to the airway under controlled circumstances (e.g., supervised, proper administration techniques), greater then negligible systemic exposure may result.…”

“…to increase the extent of systemic drug exposure over that predicted from its innate pharmacokinetic characteristics (Singh et al, 2003). Using the CYP3A4/5 substrate alfentanil, Klees et al (2005) demonstrated that ketoconazole (a commonly used azole antifungal agent) was an order of magnitude more potent than troleandomycin as an inhibitor of CYP3A4.…”

“…In the original report by Harding (1990), no unchanged FTP was detected in the plasma of volunteers up to 6 h after a 16-mg oral dose of FTP. In contrast, the majority of the FTP dose administered via inhalation is not subjected to presystemic clearance but rather is absorbed across the pulmonary vascular bed, resulting in an extent of systemic availability ranging from 14 to 31% (mean value, 21.2%) in healthy adults and 8.5 to 20.9% (mean value 13.3%) in adults with chronic obstructive pulmonary disease (Singh et al, 2003).…”

“…In the original report by Harding (1990), no unchanged FTP was detected in the plasma of volunteers up to 6 h after a 16-mg oral dose of FTP. In contrast, the majority of the FTP dose administered via inhalation is not subjected to presystemic clearance but rather is absorbed across the pulmonary vascular bed, resulting in an extent of systemic availability ranging from 14 to 31% (mean value, 21.2%) in healthy adults and 8.5 to 20.9% (mean value 13.3%) in adults with chronic obstructive pulmonary disease (Singh et al, 2003).In the original studies describing the pharmacokinetics of FTP in humans, Harding (1990) reported that up to 40% of a [ 3 H]FTP dose was converted to one principal metabolite, a 17␤-carboxylic acid derivative (M1; Fig. 1) found to have negligible pharmacological activity; the remainder of the dose was converted to several unidentified minor metabolites and glucuronide conjugates.…”