Received for publication March 24, 2008.
Revised September 15, 2008.
Accepted for publication September 17, 2008.

An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

Abstract

A number of antidepressants inhibit activity of the cytochrome P450 (CYP) 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to impact activity of CYP2D6. This single-center, randomized, open-label, 4-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/d, twice the recommended therapeutic dose for major depressive disorder in the US) and duloxetine (30 mg BID) on the pharmacokinetics of a single dose of desipramine (50 mg). Single-dose of desipramine was first given to assess its pharmacokinetics. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least square mean ratios (coadministration vs desipramine alone) for area under the plasma concentration-versus-time curve (AUC) and peak plasma concentrations (C_max) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C_max of desipramine associated with duloxetine administration (122%/63%, respectively) were significantly greater than those associated with desvenlafaxine (22%/19%, respectively; P<0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C_max that was significant compared to the small increase seen with desvenlafaxine and desipramine (-24% vs 9%; P<0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P=0.054). Overall, desvenlafaxine had a minimal impact on pharmacokinetics of desipramine compared with duloxetine, suggesting lower risk for CYP2D6-mediated drug interactions.

Key words: CYP2D, cytochrome P450, drug-drug interactions, pharmacokinetics

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