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 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 (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 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 C(max) 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.

• Authors: Albena Patroneva, Sandra M Connolly, Penny Fatato, Ron Pedersen, Qin Jiang, Jeffrey Paul, Christine Guico-Pabia, Jennifer A Isler, Michael E Burczynski, Alice I Nichols
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 36 Issue 12 Pg. 2484-91 (Dec 2008) ISSN: 1521-009X [Electronic] United States
• PMID: 18809731 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antidepressive Agents
• Cyclohexanols
• Thiophenes
• Duloxetine Hydrochloride
• Cytochrome P-450 CYP2D6
• Desipramine
• 2-hydroxydesipramine
• Desvenlafaxine Succinate

Topics

• Adult
• Antidepressive Agents (adverse effects, pharmacokinetics, pharmacology)
• Area Under Curve
• Biotransformation (drug effects)
• Cross-Over Studies
• Cyclohexanols (adverse effects, pharmacokinetics, pharmacology)
• Cytochrome P-450 CYP2D6 (drug effects, metabolism)
• Desipramine (adverse effects, analogs & derivatives, pharmacokinetics)
• Desvenlafaxine Succinate
• Drug Interactions
• Duloxetine Hydrochloride
• Female
• Humans
• Male
• Middle Aged
• Thiophenes (adverse effects, pharmacokinetics, pharmacology)