Lars Thorsson

Effects of budesonide by means of the Turbuhaler on the hypothalmic-pituitary-adrenal axis in asthmatic subjects: A dose-response study

BACKGROUND As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects. OBJECTIVES This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma. METHODS Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin. RESULTS After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo). CONCLUSIONS In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.

Systemic availability and lung deposition of budesonide via three different nebulizers in adults

BACKGROUND Budesonide is an inhaled corticosteroid widely used in the treatment of asthma. The local and systemic availability of budesonide has been determined in adults via pressurized metered-dose inhaler and dry-powder inhaler. OBJECTIVE To estimate lung deposition and systemic availability of budesonide inhalation suspension in healthy adults. METHODS Twelve adult volunteers entered an open, randomized, five-way crossover study and received the following treatments, with 1-week washout between treatments: separate 2-mg (nominal dose) budesonide doses via the Pari Inhalierboy (Inhalierboy; Pari GmbH, Starnberg, Germany), Pari LC Jet Plus (Jet Plus, Pari GmbH), and Maxin MA-2 (MA-2; Clinova Medical AB, Malmö, Sweden) jet nebulizers, 4 mg budesonide orally, and 0.5 mg budesonide intravenously. The plasma concentration of budesonide was measured up to 8 hours postadministration. Lung deposition and systemic availability of nebulized budesonide were estimated using pharmacokinetic evaluation. RESULTS In this first study of the bioavailability of budesonide inhalation suspension in adults, there were no differences between nebulizers in lung deposition (14 to 16%) or systemic availability (15 to 17%) relative to the nominal budesonide dose. Relative to the actual dose inhaled (dose-to-subject), lung deposition and systemic availability were statistically significantly higher for the Jet Plus (58 and 63%, respectively) and MA-2 (59 and 64%, respectively) nebulizers than the Inhalierboy (36 and 44%, respectively). The Inhalierboy produced larger aerosol droplets than Jet Plus or MA-2 nebulizers (7-, 5-, and 3-microm mass median diameters, respectively) and delivered a higher dose-to-subject than the other two nebulizers. CONCLUSION Relative to the nominal dose, lung deposition and systemic availability of budesonide were similar via the three nebulizers tested.

Evidence of the in vivo esterification of budesonide in human airways

AIMS Budesonide, unlike fluticasone propionate, undergoes fatty acid esterification in the lungs, and there is a need to characterize fully the distribution and fate of the two drugs after inhalation in humans. METHODS This open-label, randomized study was performed in adults undergoing whole lung or lobar resection resulting from lung cancer. Patients were given single 1000-mug doses of both budesonide and fluticasone propionate via dry powder inhalers before surgery. Tissue samples from peripheral and central lung, an ex vivo bronchial brush sample and intercostal muscle, together with plasma samples, were taken during surgery and analysed by liquid chromatography plus tandem mass spectrometry. RESULTS Lung tissue samples were obtained from 22 patients at surgery, 1-43 h after drug dosing. Budesonide was detectable from earliest sampling in central and peripheral lung tissue up to 10 h (in six of 22 samples), fluticasone propionate up to 22 h after inhalation (in 16 of 22 samples), and budesonide oleate up to 43 h after inhalation (in 21 of 22 samples). Budesonide, but not fluticasone propionate, was detected in intercostal muscle for up to 10 h after inhalation. Bronchial brush samples showed the presence of fluticasone propionate for up to 18 h, suggesting the presence of undissolved drug powder particles in the airway lumen. CONCLUSION Sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and suitability for once-daily administration.

Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers

ABSTRACT Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI‑A* 200 μg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI‑B*). Budesonide DPI‑B is available in two strengths (90 μg, 180 μg). Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI‑A and DPI‑B and test for systemic absorption bioequivalence. Methods: Adults (n =37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI‑A 200 μg × 4 inhalations, budesonide DPI‑B 180 μg × 4 inhalations, or budesonide DPI‑B 90 μg × 8 inhalations, on 3 days, each separated by a washout period of ≥ 5 days. Plasma samples were collected immediately before and up to 12 h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration–time curve from 0 to infinity (AUC0–∞) and maximum plasma concentration (Cmax); plasma concentration at 12 h (C12h) and time to maximum plasma concentration (Tmax) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC0–∞ and Cmax ratios fell between 80 and 125%. Adverse events were collected. Results: The 90% CIs for the ratios of AUC0–∞ and Cmax for budesonide DPI‑A 200 μg and DPI‑B 180 μg and for both budesonide DPI‑B strengths fell between 80% and 125% (AUC0–∞: budesonide DPI‑B 180 μg × 4/DPI‑A 200 μg × 4: 96.3% [90 % CI: 90.9, 102.1]; budesonide DPI‑B 180 μg × 4/DPI‑B 90 μg × 8: 92.2% [90 % CI: 87.0, 97.7]; Cmax: (budesonide DPI‑B 180 μg × 4/DPI‑A 200 μg × 4: 100.4% [95 % CI: 92.1, 109.4]; budesonide DPI‑B 180 μg × 4/DPI‑B 90 μg × 8: 94.4% [90 % CI: 86.6, 102.9]). No differences in C12h and Tmax were found between treatments. All treatments were well tolerated. Conclusions: Budesonide DPI‑A 200 μg and DPI‑B 180 μg have systemic absorption bioequivalence, and DPI‑B 90 μg and 180 μg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged ≥ 19 years.

Drug disposition analysis: a comparison between budesonide and fluticasone.

The characterisation of distribution and elimination properties of a drug is usually done using parameters like clearance and distributional volumes. To refine this characterisation, in this paper, we use drug disposition analysis to compare the distribution and elimination of the two glucocorticosteroids budesonide and fluticasone propionate, known to differ in this respect. This gives a more detailed description of the well known differences in distributional volumes using concepts like mean residence time and fraction of dose outside the central compartment. It clearly shows that fluticasone, although having lower plasma concentrations, still resides in the body in appreciable quantities.