Search

Three pharmacokinetic studies were performed to assess the effects of food intake and morning versus evening administration of once-daily venlafaxine extended release (XR) on the pharmacokinetic disposition of venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV). Forty-six healthy adults (43 men and 3 women), 18 to 45 years of age with body weight within 15% of normal for height and frame, were enrolled in these studies. In two studies, venlafaxine XR 75-mg or 150-mg capsules were administered to healthy subjects in fasting state or after a high-fat breakfast. In a third study, once-daily venlafaxine XR 75 mg was administered for 4 days (to steady state) either in the morning or in the evening. All three studies were conducted with a two-period crossover study design, and the plasma samples were assayed using high-performance liquid chromatography for the concentrations of venlafaxine and ODV. The steady-state pharmacokinetic profile of venlafaxine XR was not affected by the time of administration (morning or evening), and the single-dose pharmacokinetic profile was not affected by the presence or absence of food. Therefore, the venlafaxine XR formulation exhibits a controlled rate of release, and administration of venlafaxine XR with a high-fat meal does not produce a dose-dumping effect. Based on the results of these studies in healthy volunteers, once-daily venlafaxine XR 75 or 150 mg may be given without regard to meals and once-daily venlafaxine XR 75 mg may be taken either in the morning or evening without affecting the pharmacokinetic disposition of or systemic exposure to venlafaxine and ODV.

Two open-label, randomized, crossover studies, one single- and one multiple-dose, were conducted to assess the relative bioavailability of two formulations of once-daily venlafaxine extended release (XR) 75 and 150 mg compared with the immediate-release (IR) formulation of venlafaxine. Healthy adults (12 men, 12 women) aged 18 to 45 years were enrolled in each study. Frequent blood samples were taken for determination of the plasma concentrations of venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV). In the single-dose study, the 2 × 75-mg XR formulation and the 150-mg XR formulation were bioequivalent with respect to the rate and extent of absorption of venlafaxine and the formation of ODV, and the area under the plasma concentration—time curve (AUC) of both XR formulations and the AUC of the IR formulation also were bio-equivalent after normalization for dose. In the multiple-dose study, the three XR formulations were also bioequivalent with respect to the rate and extent of absorption of venlafaxine and formation of ODV, and the AUC of all three XR formulations compared with the AUC of the IR formulation also showed bioequivalence. Overall, the once-daily venlafaxine XR formulations provided the same total exposure (measured by AUC) to both venlafaxine and ODV. Thus it can be predicted that patients will obtain the same response with the XR formulations as with the IR formulations.

A single-dose, randomized, two-period, crossover study was conducted to compare the pharmacokinetics and relative bioavailability of the estrogens in Estratab® (esterified estrogens) with those in Premarin® (conjugated estrogens). Twenty-five healthy, postmenopausal women completed both study periods. Plasma concentration versus time profiles of four estrogens were examined over 48 hours using sensitive and specific gas chromatography/mass spectrophotometry/mass spectrophotometry methods. The conjugated and unconjugated estrogens generally showed slow absorption (t max , 5 to 9 hours), slow elimination (half-life, 10 to 18 hours), and lengthy mean residence times (MRT, 13 to 28 hours). The relative bioavailability (100 · AUC Estratab /AUC Premarin ) for the estrogens was 146% for total (conjugated plus unconjugated) estrone, 150% for estrone, 36% for total equilin, and 29% for equilin. Differences in peak plasma concentrations (C max ) of the estrogens were similar to the differences seen in the area under the concentration versus time curve (AUC). The time of maximum concentration (t max ) of the estrogens was approximately 1 to 2 hours shorter following Estratab administration. Estratab and Premarin have differences in the rate and extent of both the absorption of estrogens and the formation of the unconjugated metabolites. Thus these two agents cannot be considered bioequivalent, and therapeutic substitution should not be made.