title: 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.affiliation: Department of Neuroscience, Global Medical Affairs, Wyeth Research, Collegeville, PA 19426, USA.
authors.forename: Albena
authors.initials: A
authors.lastname: Patroneva
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Connolly
authors.forename: Penny
authors.initials: P
authors.lastname: Fatato
authors.forename: Ron
authors.initials: R
authors.lastname: Pedersen
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Paul
authors.forename: Christine
authors.initials: C
authors.lastname: Guico-Pabia
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Isler
authors.forename: Michael E
authors.initials: ME
authors.lastname: Burczynski
authors.forename: Alice I
authors.initials: AI
authors.lastname: Nichols
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001711:Biotransformation / Q000187:drug effects; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism*; D003891:Desipramine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000069468:Desvenlafaxine Succinate; D004347:Drug Interactions; D000068736:Duloxetine Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D003511:Cyclohexanols; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine; C028653:2-hydroxydesipramine; D000069468:Desvenlafaxine Succinate