Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation

Aims A controlled-release gastrointestinal therapeutic system (GITS) formul ation of doxazosin mesylate, a long-acting selective alpha(1)-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simpli fy the titration schedule by precisely controlling drug delivery rate, perm itting 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 therapeutical ly effective dose. The aim of the present work was to evaluate the pharmaco kinetics and bioavailability of doxazosin GITS with respect to the effect o f food, age and gender, and multiple dosing. In addition, in vitro performa nce 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 dox azosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavai lability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determi ne the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rats pro files 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 table t are independent of pH in the range of 1.2 (gastric) to 7.5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharma cology studies showed that doxazosin GITS had a lower maximum plasma concen tration, 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 r educed plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a hi gh-fat meal, the maximum plasma concentration and area under the concentrat ion-time curve were 31% and 18% higher, respectively (P < 0.05). Bioequival ence 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 elderl y subjects, and males and females, the pharmacokinetics of doxazosin GITS o nce 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 r atio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose o f 4 mg with reduced haemodynamic side-effects.