Abstract
A number of antidepressants inhibit the activity of the cytochrome P450 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 have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. 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 versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (Cmax) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and Cmax of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine Cmax that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 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 the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.
Footnotes
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This work was funded by Wyeth Research.
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Parts of this work were previously presented as a poster as follows: Germain JM, Patroneva A, Connolly SM, Fatato P, Paul J, Isler JA, Burczynski M, Guico-Pabia C, and Nichols AI (2007) An assessment of drug-drug interactions: the effects of desvenlafaxine succinate and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. 7th International Forum on Mood Anxiety Disorders; 2007 Dec 5-7; Budapest, Hungary. Wyeth Research, Collegeville, PA.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.021527.
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ABBREVIATIONS: P450, cytochrome P450; MDD, major depressive disorder; PK, pharmacokinetics; AUC, area under the plasma concentration-versus-time curve; AE, adverse event; PCR, polymerase chain reaction; LC-MS/MS, liquid chromatography-tandem mass spectrometry; QC, quality control; LSG, least-square geometric; PCI, potentially clinically important.
- Received March 17, 2008.
- Accepted September 17, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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