Abstract
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 Emax (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 viathe respiratory tract. Pharmacodynamic parameters can probably only be estimated quantitatively when the kinetics of the separate enantiomers of formoterol can be taken into account.
Footnotes
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Send reprint requests to: Prof. C. J. van Boxtel, Department of Clinical Pharmacology and Pharmacotherapy, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
- Abbreviations:
- α
- rate constant of distribution
- β
- rate constant of elimination
- A
- intercept of distribution
- B
- intercept of elimination
- AUC
- area under the curve
- Ce
- concentration in hypothetical effect compartment
- Cp
- plasma concentration
- Cmax
- maximum plasma concentration
- D
- dose
- Emax
- maximum obtainable effect
- E0
- base-line value
- EC50
- steady state concentration that gives 50% of maximum effect
- Fr
- fraction of the total amount of formoterol that appears in the systemic circulation, absorbed via the pulmonary route
- F
- bioavailability
- IgE
- immunoglobulin E
- ka
- absorption rate constant
- k21
- rate constant of drug distribution from peripheral into central compartment
- ke0
- rate constant of elimination from effect compartment
- n
- sigmoid factor
- PK/PD
- pharmacokinetic-pharmacodynamic
- t
- time after dosing
- Tmax
- time after dosing with maximum concentration
- tlag
- lagtime
- Vc
- volume of central compartment
- 1
- refers to systemic formoterol absorbedvia the lungs and upper airways
- 2
- refers to systemic formoterol absorbed via the gastrointestinal route
- Received March 17, 1997.
- Accepted July 30, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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