onizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1A adrenoceptor.
Pharmacokinetics
The pharmacokinetics of CARDURA XL are different from those of doxazosin immediate-release (IR). CARDURA XL provides a controlled release of doxazosin over a 24-hour period.
Absorption
Pharmacokinetic parameters describing absorption following 4 and 8 mg Cardura XL daily doses are reported in Table 1 below. The relative bioavailability of CARDURA XL compared with doxazosin IR was 54% at the 4 mg dose and 59% for the 8 mg dose.
TABLE 1 Mean (±SD) Plasma Concentration of Doxazosin at Steady State in Healthy Volunteers: Pharmacokinetic Parameters Parameter CARDURA XL
(4 mg) CARDURA XL
(8 mg)
Cmax (ng/mL) 10.1 ± 5.6 25.8 ± 12.1
AUC(0–∞) 183 ± 85.5 472 ± 170.8
Tmax (h) 8 ± 3.7 9 ± 4.7
Effect of Food
As illustrated in Figure 1, the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) were approximately 32% and 18% higher, respectively, after CARDURA XL was administered in the fed state compared with the fasted state. In order to provide the most consistent exposure, CARDURA XL should be administered with breakfast. (See DOSAGE and ADMINISTRATION).
Effect of GI Retention Time
Markedly reduced GI retention times (e.g. short bowel syndrome) may influence the pharmacokinetics of CARDURA XL and possibly result in lower plasma concentrations. Conversely, markedly prolonged GI retention times (e.g. chronic constipation) can increase systemic exposure to doxazosin and potentially result in increased adverse reactions (See: PRECAUTIONS; General).
Distribution
At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.
Metabolism
Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP3A4; however, CYP2D6 and CYP2C19 metabolic pathways also exist to a lesser extent. No in vivo drug interaction studies have been performed with CARDURA XL. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. (See PRECAUTIONS; Drug Interactions).
Excretion
In a study of two subjects administered radiolabeled doxazosin IR 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average, only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. The apparent elimination half-life of CARDURA XL is 15–19 hours.
Pharmacokinetics in Special Populations
Age
The effects of age on the pharmacokinetics of CARDURA XL were examined. At steady state, increases of 27% in maximum plasma concentrations and 34% in the area under the concentration-time curve were seen in the elderly (>65 years old) compared to the young (See PRECAUTIONS; Geriatric Use).
Hepatic Impairment
Administration of a single 2 mg dose of doxazosin IR to patients with mild hepatic impairment (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin compared to patients without hepatic impairment. No studies have been performed to assess the effect of hepatic |
