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Leif Bjermer,1 Piotr Kuna,2 Carin Jorup,3 Thomas Bengtsson,4 Johan Rosenborg4 1Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 2Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland; 3AstraZeneca R&D, Mölndal, Sweden; 4StatMind, Lund, Sweden Objective: The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD). Materials and methods: Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5–3200 µg) or Turbuhaler (single delivered doses of 120–1920 µg or repeated delivered once-daily doses 240–1,680 µg). AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations. Results: AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes), with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects. Conclusion: AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. These clinical trials suggest that AZD3199 is well-tolerated in healthy male volunteers and patients, with no safety concerns identified to preclude further evaluation. Keywords: AZD3199, uLABA, COPD, asthma, pharmacokinetics, tolerability

Objectives: Pharmacologically mediated bronchodilation is important in the management of asthma, and is primarily achieved with β₂-agonists. Novel compounds should preferably have a longer duration of action and a better systemic side effect profile than established alternatives at comparable peak bronchodilation. This single-dose crossover study was conducted to investigate and compare with formoterol the bronchodilatory and systemic effects, tolerability and safety of AZD3199, a novel ultra-long-acting β₂-agonist (uLABA)., Methods: Patients with asthma (n = 37) were randomized to receive AZD3199 (120, 480, 1920 µg), formoterol (9, 36 µg) or placebo inhaled via a Turbuhaler™. Bronchodilation was evaluated by maximum (E(max)) and average 22-26 h (E₂₂₋₂₆) forced expiratory volume in 1 second (FEV1). Serum potassium was evaluated by minimum (E(min)) and 0-4 h average (E(av)) determined from serial measurements. AZD3199 and formoterol were compared on the basis of relative dose potency. Adverse events, clinical laboratory tests and physical examinations were markers for safety and tolerability, with plasma AZD3199 as the indicator of drug exposure., Results: All active treatments dose-dependently increased E(max) and AZD3199 (480 and 1920 µg) and formoterol (36 µg) significantly increased E(₂₂₋₂₆) versus placebo. Relative dose potency between AZD3199 and formoterol was 50-fold on the microgram scale with respect to E max and 11-fold with respect to E(₂₂₋₂₆). Small, dose-dependent effects on potassium, heart rate and QTc were seen after administration of AZD3199 compared with placebo. These well-known dose-related class effects of β₂-agonists were mild. Notably, serum potassium suppression was less pronounced after AZD3199 compared with formoterol at similar bronchodilation. Overall, AZD3199 was well tolerated., Conclusions: AZD3199 480 µg and 1920 µg produced 24-hour bronchodilation. At comparable peak bronchodilator effect, AZD3199 was associated with a lower level of systemic side effects than formoterol. AZD3199 was well tolerated, with no safety concerns identified to preclude further investigation. ClinicalTrials.gov study identifier: NCT00736489.

The single-dose effect of formoterol racemate and enantiomers on bronchodilatation up to 24 h was determined. Forty-six reversible asthmatic patients were randomised to this double blind, crossover study. Formoterol was inhaled by nebulizer (HaloLite); 4.5 and 36 microg of the racemate (rac-formoterol), 2.25 and 18 microg of (R;R)-formoterol, 18 mirog of (S;S)-formoterol, or placebo. Airway and systemic effects were assessed by serial measurements of forced expiratory volume during the first second, FEV1 (24 h), and heart rate (4 h). Rac- and (R;R)-formoterol significantly and dose-dependently increased FEV1 with similar mean maximal effect. (S;S)-formoterol was without significant effects on FEV1 and heart rate. (R;R)- and rac-formoterol were still effective 22-24 h after single high doses, but this was associated with some systemic side effect (increased heart rate) initially. Average 22-24 h FEV1 was 8% (rac-formoterol 36 microg) and 11% ((R;R)-formoterol 18 microg) over placebo, respectively. No significant differences in effects were observed between rac- and (R;R)-formoterol. Thus, the single dose bronchodilatating effect of formoterol resides in (R;R)-formoterol. This study does not indicate a clinically important advantage of (R;R)-formoterol as acute bronchodilator compared to the racemate.

Objectives: To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children., Methods: Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxis) 4.5 microg (F4.5) or terbutaline (Bricanyl) 500 microg (T500) were inhaled cumulatively via a dry powder inhaler (Turbuhaler) over 1 h (three patients) or 2.5 h (17 patients) and compared to a day of no treatment, in a randomised, double-blind (active treatments only), crossover trial. Blood pressure (BP), ECG, plasma potassium, glucose, lactate, and adverse events were monitored up to 10 h to assess tolerability and relative systemic dose potency., Results: Formoterol and terbutaline had significant beta2-adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration and PR interval, the systemic effects were significantly more pronounced with terbutaline than with formoterol. Thus, mean minimum plasma potassium, was suppressed from 3.56 (95% confidence interval, CI: 3.48-3.65) mmol l(-1) on the day of no treatment to 2.98 (CI: 2.90-3.08) after 10 x F4.5 and 2.70 (CI: 2.61-2.78) mmol l(-1) after 10 x T500, and maximum Q-Tc (heart rate corrected Q-T interval [Bazett's formula]) was prolonged from 429 (CI: 422-435) ms on the day of no treatment, to 455 (CI: 448-462) ms after 10 x F4.5 and 470 (CI: 463-476) ms after 10 x T500. Estimates of relative dose potency indicated that F4.5 microg had the same systemic activity as the clinically less effective dose of 250 microg terbutaline. The duration of systemic effects differed marginally between treatments. Spontaneously reported adverse events (most frequently tremor) were fewer with formoterol (78% of the children) than with terbutaline (95%). A serious adverse event occurred after inhalation of 45 microg formoterol over the 1 h dosing time, that prompted the extension of dosing time to 2.5 h., Conclusions: Multiple inhalations over 2.5 h of formoterol (4.5 microg) via Turbuhaler) are at least as safe as and associated with less systemic effects than multiple inhalations of the clinically equipotent dose of terbutaline (500 microg) in children with asthma., (Copyright 2004 Blackwell Publishing Ltd)

Objective: To quantify the relation between local and systemic magnitudes of effects of inhaled formoterol and salbutamol., Methods: Twenty-eight stable asthmatic patients completed this double-blind, randomised crossover study. Pre-drug administration FEV1 (mean 2.08 L) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutanmol. Patients inhaled three single doses of formoterol fumarate dihydrate (Oxis) (delivered doses of 4.5, 18 and 54 microg) via Turbuhaler, two single doses of salbutamol (200 and 1800 microg) via a pressurised metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. A classic sigmoid model of log-dose response was used to discriminate pharmacologically between formoterol and salbutamol. Relative local (maximum FEV1) and systemic (minimum S-KC) dose potencies, and their ratio, the relative therapeutic index, were estimated using an on-linear mixed effect model., Results: The drug effects were well tolerated and dose dependent The bronchodilating effect was on a part of the dose response curve that could be well approximated by a log-linear function, the serum potassium suppressing effect sometimes was not (the lowest doses differed only marginally from placebo). Thus, a log-linear approximation was used to describe bronchodilation, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index was estimated to be 2.5 (95%confidence interval: 0.9-6.5)., Conclusions: The mean relative therapeutic index between formoterol (Oxis) 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to 2.5 in favour of formoterol; this trend was not statistically significant.

Aims: The pharmacokinetics of orally administered bambuterol were investigated in healthy adult subjects, with particular regard to time to steady state, pharmacokinetic linearity, intraindividual variability for the parent drug and its active beta2-adrenergic metabolite terbutaline and bioequivalence between tablet and solution., Methods: Twenty-six healthy Caucasian subjects were included and 23 (12 women) completed this open, randomised, crossover study. Racemic bambuterol hydrochloride was administered orally as 10 mg, 20 mg, and 10 + 20 mg tablets, and as a solution once daily for 2 weeks at about 19.00 h. Plasma concentrations and urinary recoveries of bambuterol and terbutaline were measured after single doses and during repeated treatments., Results: Absorption of bambuterol was biphasic. The initial rate could not be assessed directly, but it was faster than that during the second phase where absorption was rate-limiting for elimination (mean terminal half-life: 16 h). Steady-state AUC(0,24 h) of bambuterol, reached within 1 week, was not dose-linear. Mean terminal half-life of terbutaline was 22 h and steady-state was reached within one week of bambuterol treatment. Contrary to bambuterol, overall pharmacokinetics of terbutaline indicated dose-linearity. Day-to-day intraindividual variation in AUC(0,24 h) of terbutaline, 15% with the tablet, was half that of bambuterol. Urine data indicated that intraindividual variability was slightly smaller with the solution. Tablets were bioequivalent with the solution with regard to terbutaline (90% confidence interval: 87-100%)., Conclusions: With oral bambuterol steady state was reached within 1 week. Regarding generated terbutaline, pharmacokinetics judged to be were linear, intraindividual variability of AUC at steady state was on average 15% with the tablet, and tablets were bioequivalent with the solution.

Mass balance and metabolism of formoterol were investigated in six healthy men in an open study. Mean age was 49.7 years (range: 40-63). Simultaneous oral (mean dose 88.6 nmol, 49.3 MBq) and i.v. (mean dose 38.2 nmol, 21.4 MBq) doses of tritium-labeled formoterol were administered. The combination of these two administrations was aimed at simulating the fate of inhaled formoterol. Total radioactivity was monitored for 24 h in blood plasma and for at least 4 days in urine and feces. Formoterol and metabolites were determined using liquid chromatography plus radiodetection, directly after centrifugation in urine and after sample workup in blood plasma and feces. Metabolites were identified in urine, sampled from two subjects, using liquid chromatography-electrospray ionization mass spectrometry. Mean total recovery was 86% of the administered formoterol dose, 62% in urine and 24% in feces. Tritiated water was generated and because its in vivo turnover is slow, the terminal decline of total radioactivity was slow and dose recovery was incomplete during the sampling period. Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low. O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7. 0% in urine and 2.0% in feces.

Aims: To investigate dose proportionality, dosing frequency, and ethnic aspects of the pharmacokinetics of bambuterol in asthmatic children, and to discuss the relationship with previous observations in adults., Methods: Forty-eight children in four different studies completed two double-blind bambuterol treatments each (daily doses of bambuterol hydrochloride): 12 preschool (5 mg x 2 vs 10 mg) and 12 school (10 mg vs 20 mg) Caucasians, 12 preschool (2.5 mg vs 5 mg), and 12 school (10 mg vs 20 mg) Orientals. Peak plasma concentrations and dosing interval area under curve (AUC) of bambuterol and the active metabolite terbutaline were assessed at steady state. Treatment differences were analysed statistically within each study. Differences between the studies and the relation to steady-state AUC in adults were described., Results: Dose proportionality was seen for terbutaline but not for bambuterol. Twice-daily dosing (2 x AUC(0,12 h)) could not be shown to differ from once-daily dosing (AUC(0,24 h)) in the preschool Caucasians. Mean AUC of terbutaline was 128 and 242 nmol l-1 h in the preschool Caucasians (5 mg/12 h; 10 mg/24 h), 213 and 406 nmol l-1 h in the Caucasian school children (10 mg; 20 mg), 87.4 and 202 nmol l-1 h in the Oriental preschool children (2.5 mg; 5 mg), and 356 and 640 nmol l-1 h in the Oriental school children (10 mg; 20 mg). Oriental school children had higher plasma concentrations of bambuterol and terbutaline than Caucasian school children. The strict ethnic implication of the difference could not be elucidated, because demographic data were not perfectly matched. Terbutaline AUC was only moderately increased in the Caucasian school children compared with Caucasian adults. The increase was more pronounced in Oriental children and in some preschool Caucasians. The highest concentration of terbutaline, 58 nmol l-1, was seen in an Oriental school child after a 20 mg dose., Conclusions: Caucasian school children can be given bambuterol hydrochloride very much as Caucasian adults, 10 or 20 mg once daily, but Oriental preschool and school children plus preschool Caucasians should be given lower doses.

Aims: It has been assumed that both plasma cholinesterase (EC 3.1.1.8) and oxidative enzymes are needed for optimum formation of the bronchodilator terbutaline from its biscarbamate prodrug bambuterol. The present study aimed at investigating the fate of bambuterol in subjects with deficient plasma cholinesterase but with normal oxidative (CYP2D6) capability., Methods: The pharmacokinetics of bambuterol and terbutaline were studied in four healthy subjects (two men and two women) being homozygous for the atypical gene for plasma cholinesterase. Their oxidative metabolism was apparently good as they were all rapid metabolizers of debrisoquine. Bambuterol hydrochloride 20 mg was given orally once daily for 10 days, and plasma and urine samples were taken for 1.5 days (plasma) and 4.5 days (urine) after administration of the last dose., Results: The pharmacokinetic parameters in the present study were grossly similar to those found in a study of bambuterol in subjects with normal plasma cholinesterase activity (N). However, subjects with atypical cholinesterase had a shorter terminal half-life of bambuterol (a measure of uptake rate), 4.8-12.6 h vs 8.3-22.3 h in N, and slightly higher plasma concentrations of bambuterol (average concentrations 1.9-3.7 nmol l(-1) vs 1.5-3.1 nmol l(-1) in N). Peak/trough terbutaline plasma concentrations ratios (2.1-3.2) were somewhat increased, but average plasma concentrations (8.3-14.5 nmol l(-1)) and terminal half-life (16.5-21.8 h) of terbutaline did not differ., Conclusions: In Caucasian populations, one subject out of 2500 is homozygous for the atypical gene for plasma cholinesterase. The atypical enzyme has a much lower affinity for bambuterol than the normal enzyme. Nevertheless, the subjects with atypical cholinesterase were able to produce terbutaline as efficiently as normal subjects. This might be explained by an altered uptake and metabolism in the absence of plasma cholinesterase, or the importance of this enzyme for the formation of terbutaline from bambuterol in vivo may have been overestimated.

Aims: To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjects., Methods: Eight healthy subjects (four women) received intravenous doses of bambuterol and terbutaline. On a third occasion, they, plus another four subjects, ingested oral bambuterol as a single dose followed by repeated doses once daily for 7 days. Plasma concentrations and urinary excretion of bambuterol and terbutaline were measured., Results: After intravenous administration, renal clearances of bambuterol and terbutaline were similar (about 140 ml min(-1)), but there was a five-fold difference in total clearance (bambuterol 1.25 l min(-1), terbutaline 0.23 l min(-1)). Volume of distribution (Vss) was 1.6 l kg(-1) b.w. for both substances. A similar renal clearance of bambuterol was found during oral administration but that of terbutaline decreased (to about 120 ml min(-1)). Mean terminal half-life of bambuterol was 2.6 h after intravenous and 12 h after oral administration, implying that uptake was rate-limiting. Mean residence time of terbutaline generated from oral bambuterol was 34 h compared with 8.0 h when terbutaline as such was infused. Generated terbutaline had a bioavailability of 36% (28-46) after intravenous and 10.2% (6.1-13.2) after oral administration of the prodrug. Bambuterol was well tolerated. The mean activity of plasma cholinesterase, an enzyme catalyzing bambuterol metabolism, was inhibited between 30-60% during repeated oral dosing. It virtually regained original activity within 48 h after the last dose., Conclusions: The plasma concentration ofterbutaline fluctuated little during repeated oral administration (mean peak: trough ratio 1.9), as a result of prolonged absorption of bambuterol and slow formation of terbutaline. Thus, the pharmacokinetic properties of bambuterol make it suitable for oral once-daily dosage.

The validity of a simplified diagnostic aid, Oricult-N, for detection of oral candidoses was compared with smears stained according to the periodic acid-Schiff's method. Samples were taken from 80 locations in 36 patients with lesions suspected for candidal infection. There was a statistically significant correlation between the two methods (P less than 0.001).