Pharmacokinetic/dynamic correlation of pulmonary and cardiac effects of fenoterol in asthmatic patients after different routes of administration.

Pulmonary and cardiac effects of the beta 2-adrenergic drug fenoterol were studied in 27 asthmatic patients using an integrated pharmacokinetic/dynamic (PK/PD) approach. Airway resistance (Rf), intrathoracic gas volume (IGV), heart rate, and plasma levels were monitored after placebo, injection (12.5 and 25 micrograms), nasal instillation (400 micrograms), inhalation (200 and 400 micrograms), and infusion (200 micrograms/180 min with or without loading dose). The pharmacokinetics were best described by an open three-compartment model with a terminal half-life of 200 min (gamma = 0.23 +/- 0.08 L/hr), a volume of distribution at steady state of 1.9 +/- 0.8 L/kg, and a clearance of 0.86 +/- 0.32 L/hr/kg, with 14 and 9% absorbed after nasal and pulmonary administration, respectively. For the noninhalation regimens, a PK/PD correlation linked the concentration in the shallow pharmacokinetic compartment to the investigated effects via an Emax relationship, resulting in three to five times higher EC50 values (concentration necessary to achieve half-maximal effect) for the heart rate than for the beta 2-mediated effects on IGV and Rf. In contrast, pulmonary effects after inhalation could not be incorporated into the correlation, indicating that these effects are induced locally after inhalation. Intrapatient variability for EC50 and Emax was approximately 90%.