Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary

The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.

Disposition after i.v. administration was described by a clearance of 0.54 l·min⁻¹, central compartment volume of 14.8 l, distribution rate constant 0.092 min⁻¹, and an elimination rate constant of 0.0044 min⁻¹. The corresponding estimates after i.m. administration were 0.324 l·min⁻¹, 34.1 l, 0.035 min⁻¹, and 0.0018 min⁻¹. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml⁻¹ and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml⁻¹, and 9 min.

Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min⁻¹, with an EC₅₀ of 176 ng·ml⁻¹ and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min⁻¹, 250 ng·ml⁻¹, and 3 min.

The optimal plasma concentration of thiazinamium was about 100 ng·ml⁻¹, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min⁻¹.