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Clinical Pharmacology
CLINICAL PHARMACOLOGY
Pharmacodynamics The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Text Continues Below
Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or 1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/ day. Mean SD steady-state plasma clearance of venlafaxine and ODV is 1.3 0.6 and 0.4 0.2 L/ h/ kg, respectively; apparent elimination half-life is 5 2 and 11 2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5 3.7 and 5.7 1.8 L/ kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27 and 30 , respectively). Absorption Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92 of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45 . Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/ mL for venlafaxine and 260 ng/ mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (Cmax's for immediate release 75 mg q12 hours were 225 ng/ mL for venlafaxine and 290 ng/ mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, provides a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet. Page: 1 | 2 | 3 | 4 | 5 | Next >>
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