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Background and Objective: Desvenlafaxine (administered as desvenlafaxine succinate) is approved for the treatment of major depressive disorder (MDD). If eliminated by the kidney, desvenlafaxine may have more favorable pharmacokinetic or drug-drug interaction profiles compared to its parent compound, venlafaxine, which depends primarily on the CYP2D6 enzyme system. Therefore, the pharmacokinetics and bioavailability of desvenlafaxine was assessed in healthy human subjects. Methods: In a single-dose, open-label, crossover study, subjects were randomly assigned to 100 mg/d of oral desvenlafaxine or intravenous (50 mg/1 hr) desvenlafaxine. Plasma and urine were collected for 72 hours postdosing and assayed to determine pharmacokinetics and bioavailability of (R)-, (S)-, and (R+S)-desvenlafaxine and N,O-didesmethylvenlafaxine. Results and Discussion: Pharmacokinetic parameters for (R)-and (S)-desvenlafaxine enantiomers were approximately equivalent for the oral and intravenous formulations of desvenlafaxine. Compared with 50 mg intravenous desvenlafaxine, 100 mg oral desvenlafaxine had a higher area under the plasma concentration-time curve and an absolute bioavailability of 80.5%. Urinary excretion of total desvenlafaxine and N,O-didesmethylvenlafaxine accounted for 69% of the orally administered desvenlafaxine dose, with the majority of a dose being excreted unchanged or as the glucuronide conjugate (66%). Conclusion: Desvenlafaxine has high oral bioavailability and provides an evenly balanced enantiomeric ratio.

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The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.