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Aims: To assess the mechanistic relationship between doxazosin (alpha(1)-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 alpha(1)-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 alpha(1)-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 alpha(1)-receptor antagonists. Receptor occupancy is a useful index for predicting the clinical effects of alpha(1)-receptor antagonists.

Aims: A controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simplify the titration schedule by precisely controlling drug delivery rate, permitting an initial dose of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg day-1 and titrated to a higher therapeutically effective dose. The aim of the present work was to evaluate the pharmacokinetics and bioavailability of doxazosin GITS with respect to the effect of food, age and gender, and multiple dosing. In addition, in vitro performance was assessed in conditions simulating the gastrointestinal environment., Methods: A three-way crossover study in 24 subjects assessed the comparative bioavailability of doxazosin GITS under fed and fasting conditions and doxazosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determine the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rate profiles of doxazosin GITS were determined in artificial gastric fluid (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the dissolution characteristics of doxazosin GITS in artificial gastric fluid was studied at stirring rates of 50, 75, and 100 rev min-1., Results: In vitro studies demonstrated that release rates for the GITS tablet are independent of pH in the range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharmacology studies showed that doxazosin GITS had a lower maximum plasma concentration, prolonged time to reach maximum plasma concentration, and a higher minimum plasma concentration compared with doxazosin standard. Thus, the GITS formulation results in a more gradual absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a high-fat meal, the maximum plasma concentration and area under the concentration-time curve were 31% and 18% higher, respectively (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult and elderly subjects, and males and females, the pharmacokinetics of doxazosin GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in the subjects studied, including young and elderly males and females., Conclusions: The GITS formulation of doxazosin enhances the pharmacokinetic profile compared with doxazosin standard, allowing more gradual absorption of doxazosin, and a reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic side-effects.

This study in 12 normotensive males investigated potential pharmacokinetic and pharmacodynamic interaction mechanisms resulting from the combination of enalapril and doxazosin. Blood pressure reductions were consistently greater with the combination but there was no evidence of a significant pharmacodynamic interaction (as determined by heart rate changes, renal function tests or by pressor responsiveness indices) and there was no evidence of a pharmacokinetic interaction with either drug. Responsiveness to each drug i.e. blood pressure reduction per unit drug concentration was not significantly altered in the combination regimen. In conclusion, these results suggest that the combination of enalapril and doxazosin produces a usefully additive hypotensive effect but there was no evidence of synergism i.e an effect which was more than additive.