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. Air-way resistance (R(f)) intrathoracic gas volume (IGV), heart rate, and plasma levels were monitored after placebo, injection (12.5 and 25-mu-g), nasal instillation (400-mu-g), inhalation (200 and 400-mu-g), and infusion (200-mu-g/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 E(max) 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 R(f). 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 E(max) was approximately 90%.