Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler (R)

Aims The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 mu g, 800 mu g or 1600 mu g administered twice daily by a dry-powder inhaler (Turbuhaler(R )) in adult patients with mild asthma. Methods A total of 38 patients received budesonide by inhalation, 13 receiv ed 400 mu g hvice daily, 12 received 800 mu g twice daily and 13 received 1 600 mu g twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.91 min(-1) in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatograp hy plus mass spectrometry. Results Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (t(max)) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid el imination with a half-life of approximately 3 h. C-max was 1.4(2.0) nmol l( -1) (single (repeated) doses), 2.6(3.6) nmol l(-1) and 5.4(6.4) nmol l(-1) after 400, 800 and 1600 mu g twice daily, respectively. The corresponding r esults for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l(-1) min. Ninety percent confidence intervals for pairwise dose-normalized C-max and AUC comparisons between g roups were large but contained unity in all cases, thus indicating dose-pro portional pharmacokinetics. Regression on analysis supported these findings . Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0,infinity,SD)(P=0.04) with no si gnificant differences between doses, indicating slight accumulation followi ng bid dosing. Conclusions In this relatively small study, budesonide inhaled via Turbuhal er(R) appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients.