Vol. 283, Issue 2, 824-832, 1997

Biphasic Effect-Time Courses in Man after Formoterol Inhalation: Eosinopenic and Hypokalemic Effects and Inhibition of Allergic Skin Reactions

M. G. M. Derks, B. T. J. van den Berg, J. S. van der Zee, M. C. P. Braat and C. J. van Boxtel

Department of Clinical Pharmacology and Pharmacotherapy (M.D., B.v.d.B., C.v.B.) and Department of Pulmonology (J.v.d.Z., M.B.), Academic Medical Center, Amsterdam, The Netherlands

The kinetics of inhaled racemic formoterol and its effects on the size of the early cutaneous reaction to intradermal injection of an allergen, eosinopenia and hypokalemia were assessed by pharmacokinetic-pharmacodynamic modeling. After inhalation of either 120 µg of formoterol or placebo, blood samples were taken and skin tests were performed in seven healthy subjects. A two-compartment model was needed to describe the observed formoterol plasma concentration-time curves. To describe the observed biphasic concentration, two absorption routes with different absorption rate constants were incorporated in the model. These two phases were explained by rapid absorption via the respiratory tract together with a slower and delayed oral absorption. For the description of the concentration-effect relations, an E_max (the maximum obtainable effect) formula for competitive agonism, with an effect compartment, had to be used. Fitting the wheal and flare, an apparent diurnal variation had to be taken into account by incorporating in the model rising base-line values. For the flare responses, influence of the location on the forearm appeared to be operative. Systemic formoterol absorbed via the oral route behaved differently from the fraction absorbed via the lungs, with EC₅₀ (steady state concentration that gives 50% of maximum effect) values for all three systemic effects being three times lower after oral absorption than after absorption via the respiratory tract. Pharmacodynamic parameters can probably only be estimated quantitatively when the kinetics of the separate enantiomers of formoterol can be taken into account.