Assessment of α₁-adrenoceptor antagonists in benign prostatic hyperplasia based on the receptor occupancy theory

Aims: To assess the mechanistic relationship between doxazosin (α₁-receptor antagonist) and receptor occupancy and a measure of pharmacological effect (Q_max, the maximum urinary flow rate) and to compare the mean receptor occupancy ratio at clinical doses of doxazosin, tamsulosin, terazosin and prazosin in benign prostatic hyperplasia (BPH). Methods: A ternary complex model, which described the mechanism of α₁-receptor antagonists, was fitted to the pharmacological effects and receptor occupancy ratio data for doxazosin (standard tablet). In addition, mean receptor occupancy was calculated for other α₁- receptor antagonists and the optimal receptor occupancy was evaluated. The clinical pharmacological effects of the controlled release formulation of doxazosin (doxazosin GITS) were estimated based on the receptor occupancy. Results: The mechanistic based model was able to describe the pharmacological effects of doxazosin. Regardless of the plasma concentrations or clinical dose of each drug, the results suggest that receptor occupancy is useful to assess quantitatively and compare the pharmacological effects of drugs with similar mechanisms of action. The clinical dosage for doxazosin GITS was estimated to be at least 8 mg and the stable pharmacological effect is expected based on the estimated receptor occupancy. Conclusions: A model for Q_max improvement in BPH based on the receptor occupancy theory was able to describe the clinical effects of the α₁-receptor antagonists. Receptor occupancy is a useful index for predicting the clinical effects of α₁-receptor antagonists.