title: The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults.
abstract: The potential for cytochrome P450 (CYP) 2D6 substrates to interact with desvenlafaxine (administered as desvenlafaxine succinate) and paroxetine was evaluated. In an open-label, crossover study, 20 healthy volunteers (aged 21-50) were randomized to 2 series of 9 days each of desvenlafaxine (100 mg/d) or paroxetine (20 mg/d), separated by a 5-day washout. The CYP2D6 substrate desipramine (50 mg) was administered alone on day 1 and coadministered on day 6 of dosing with either desvenlafaxine or paroxetine. CYP2D6 genotype was determined at baseline. Based on least squares geometric mean ratios between reference (desipramine alone) and test treatments, desvenlafaxine produced minor increases in desipramine area under the plasma concentration versus time curve (AUC; 36%) and peak plasma concentration (C(max); 30%) (vs paroxetine: 419%, 90%, respectively; both P < .001). Desvenlafaxine produced little change in 2-hydroxydesipramine AUC (16% increase) and C(max) (0%) versus paroxetine (18% and 82% decreases, respectively; P = .008, P < .001, respectively), indicating that desvenlafaxine, especially at the recommended therapeutic dose of 50 mg/d for major depressive disorder in the United States, has little potential to interact with CYP2D6 substrates.
authors.affiliation: Wyeth Pharmaceuticals, 500 Arcola Rd, Collegeville, PA 19426, USA. nicola2@wyeth.com
authors.forename: Alice I
authors.initials: AI
authors.lastname: Nichols
authors.forename: Penny
authors.initials: P
authors.lastname: Fatato
authors.forename: Magdy
authors.initials: M
authors.lastname: Shenouda
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Paul
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Isler
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Pedersen
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Saeeduddin
authors.initials: S
authors.lastname: Ahmed
authors.forename: Albena
authors.initials: A
authors.lastname: Patroneva
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000494:pharmacology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000069468:Desvenlafaxine Succinate; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology*; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D003511:Cyclohexanols; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D017374:Paroxetine; D003891:Desipramine; C028653:2-hydroxydesipramine; D000069468:Desvenlafaxine Succinate