Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three-period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O-desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady-state elimination half-life was 3 to 4 hours for venlafaxine and 10 hours for O-desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral-dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O-desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O-desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor.AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high-clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose-proportionality.

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ObjectivesDisability is considered an important issue that affects the elderly population. This study aimed to explore the relationship between disability and all-cause mortality in US elderly individuals.DesignRetrospective and longitudinal designs.SettingData from the National Health and Nutrition Examination Survey (NHANES 1999–2002) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention.ParticipantsA total of 1834 participants in the age range 60–84 years from NHANES 1999–2002.Main outcome measuresWe acquired five major domains of disability (activities of daily living (ADL), general physical activities (GPA), instrumental ADL (IADL), lower extremity mobility (LEM) and leisure and social activities (LSA)) through self-reporting. We applied an extended-model approach with Cox (proportional hazards) regression analysis to investigate the relationship between different features of disability and all-cause mortality risk in the study population.ResultsDuring a mean follow-up of 5.7 years, 77 deaths occurred. An increased risk of all-cause mortality was identified in elderly individuals with disability after adjustment for potential confounders (HR 2.23; 95% CI 1.29 to 3.85; p=0.004). Participants with more than one domain of disability were associated with a higher risk of mortality (ptrend=0.047). Adjusted HRs and 95% CIs for each domain of disability were 2.53 (1.49 to 4.31), 1.99 (0.93 to 4.29), 1.74 (0.72 to 4.16), 1.57 (0.76 to 3.27) and 1.52 (0.93 to 2.48) for LEM, LSA, ADL, IADL and GPA, respectively.ConclusionsThe results of this study support an increased association between disability and all-cause mortality in the elderly in the USA. Disability in LEM may be a good predictor of high risk of all-cause mortality in elderly subjects.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.