Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 256 _____________________________ _____________________________ Clinical-Pharmacokinetic Aspects of Prolonged Effect Duration as Illustrated by β2-Agonists BY JOHAN ROSENBORG ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) Pharmacokinetics and Drug Therapy presented at Uppsala in 2001 ABSTRACT Rosenborg, J. 2001. Clinical-Pharmacokinetic Aspects of Prolonged Effect Duration as Illustrated by β2-Agonists. Acta Univ. Ups. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 256. 41 pp. Uppsala. ISBN 91-554-5099-7. Regularity is a key element of maintenance drug treatment; compliance is crucial for treatment success. Once- or twice-daily intake of a drug is always easier to comply with than regimens requiring more frequent dosing. Bronchodilating treatment was used as an example to illustrate how sustained duration of effect can be achieved by two different approaches: oral administration of the terbutaline prodrug bambuterol and inhalation of formoterol. Bioanalytical methods were employed to monitor the kinetic fate of bambuterol and formoterol in plasma, urine, or faeces. Generated terbutaline in plasma was used as a marker of effect for bambuterol. Established clinical laboratory tests were used to assess local and systemic effects of inhaled formoterol compared with salbutamol. Recommended doses of bambuterol, 10-20 mg once daily in adults, normally produced plasma concentrations of the active moiety terbutaline within therapeutically relevant limits. Dose proportionality for terbutaline makes dosing with bambuterol predictable. Compared with adults, children should be given higher doses than indicated by their lower body weight. Pharmacokinetic analysis indicated that absorption of bambuterol was slow and multi-phasic and that slow biotransformation to terbutaline occurred both presystemically and systemically. Systemically circulating formoterol was rapidly eliminated, the inactive (S;S)-formoterol more rapidly than the active (R;R)-formoterol. An inactive phenol glucuronide was the main metabolite, and a previously unknown sulphate metabolite was discovered. Duration of systemically mediated cardiovascular or metabolic side-effects of inhaled formoterol seemed not to differ from those of an inhaled systemically equieffective dose of salbutamol. There was a trend suggesting that the magnitude of systemic side-effects may be less pronounced after inhalation of formoterol compared with a locally equieffective dose of inhaled salbutamol. Both approaches to sustaining stimulation of β2-adrenoceptors have their pros and cons. Bambuterol can be dosed orally once daily, but full effect is reached slowly. The effect of formoterol is reached within a few minutes, but administration must occur via the lungs, often twice daily. Both treatments, however, give 24-h symptom relief during regular treatment. Johan Rosenborg, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, BMC, Box 591, SE-751 24 Uppsala, Sweden and Experimental Medicine, AstraZeneca R&D Lund, SE-221 87 Lund, Sweden Johan Rosenborg 2001 ISSN 0282-7484 ISBN 91-554-5099-7 Printed in Sweden by Lindbergs Grafiska HB, Uppsala 2001 PAPERS DISCUSSED This thesis is based on the following papers, which will be referred to in the text by their Roman numerals. I. Rosenborg J, Larsson P, Nyberg L. Pharmacokinetics of bambuterol during oral administration of plain tablets and solution to healthy adults. Br J Clin Pharmacol 2000;49:199-206. II. Ahlström H, Alvero J, Alvero R, et al. Pharmacokinetics of bambuterol during oral administration to asthmatic children. Br J Clin Pharmacol 1999;48:299-308. III. Rosenborg J, Larsson P, Tegnér K, Hallström G. Mass balance and metabolism of 3H-formoterol in healthy men after combined i.v. and oral administration - mimicking inhalation. Drug Metab Dispos 1999;27:1104-1116. IV. Rosenborg J, Bengtsson T, Larsson P, Blomgren A, Persson G, Lötvall J. Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics. Eur J Clin Pharmacol 2000;56:363-370. V. Rosenborg J, Larsson P, Rott Z, Böcskei C, Poczi M, Juhász G. Assessment of a relative therapeutic index between inhaled formoterol and salbutamol in asthma patients. Submitted 2001. ABBREVIATIONS USED IN FRAME STORY Ae Amount excreted in urine during a collection interval ANOVA Analysis of variance AUC Area under the curve of plasma concentration vs time CLA Apparent clearance after oral administration (dependent also on bioavailability) CLR Renal clearance ESI Electrospray ionization FEV1 Forced expiratory volume (L) in the first second 3 H2O Tritiated water F Formoterol FG1 Phenol glucuronide of formoterol FG2 Benzyl glucuronide of formoterol FS Sulphate of formoterol S-K+ Serum concentration of the potassium ion LC Liquid chromatography LOQ Limit of quantification Met1 O-demethylated formoterol Met1G1 Phenol glucuronide 1 of O-demethylated formoterol Met1G2 Phenol glucuronide 2 of O-demethylated formoterol Met2S Sulphate of deformylated formoterol MS Mass spectrometry Q-Tc Q-T interval corrected for heart rate (R;R)/(S;S) Ratio of formoterol enantiomers in urine T½ Terminal half-life Total Total radioactivity: the sum of formoterol plus metabolites and tritiated water excreted in urine and faeces XTOT Quantified unidentified metabolites of formoterol CONTENTS INTRODUCTION......................................................................................................................................7 BASIC PHARMACOLOGY OF β2-AGONISTS....................................................................................7 STRUCTURE, ACTIVITY, AND SELECTIVITY ...............................................................................................7 PULMONARY PHARMACOLOGY .................................................................................................................9 EXTRAPULMONARY PHARMACOLOGY ......................................................................................................9 METABOLIC EFFECTS..............................................................................................................................10 THE RELATION BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS ...........................................10 PHARMACOKINETIC QUALITIES OF LONG-ACTING β2-AGONISTS..............................................................10 PROLONGED DURATION OF BRONCHODILATION – PREVIOUS RESULTS........................12 PROLONGED SYSTEMICALLY-MEDIATED EFFECT OF THE SHORT-ACTING β2-AGONIST TERBUTALINE USING PRODRUGS ..............................................................................................................................................12 PHARMACOKINETIC BASIS OF PROLONGED TOPICALLY-MEDIATED EFFECT .............................................15 PRESENT INVESTIGATION................................................................................................................17 OBJECTIVES............................................................................................................................................17 METHODS ...............................................................................................................................................17 Pharmacokinetics of bambuterol......................................................................................................17 Fitting a pharmacokinetic model to previous data on bambuterol................................................................ 17 Study designs ............................................................................................................................................... 18 Bioanalysis................................................................................................................................................... 19 Calculations and primary statistical analyses............................................................................................... 20 Pharmacokinetics and effects of formoterol .....................................................................................21 Study designs ............................................................................................................................................... 21 Effect measurements and bioanalysis........................................................................................................... 22 Calculations and primary statistical analyses............................................................................................... 23 RESULTS.................................................................................................................................................24 Pharmacokinetic modelling of previous data on bambuterol...........................................................24 Pharmacokinetics of bambuterol tablets and solution (Papers I and II)..........................................25 Mass balance and metabolism of 3H-formoterol in healthy men (Paper III) ...................................28 Relative systemic dose potency and tolerability of inhaled formoterol and salbutamol in healthy subjects and asthmatics (Paper IV) ..................................................................................................29 Assessment of a relative therapeutic index between inhaled formoterol and salbutamol