title: Effects of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults.
abstract: The results of two single-center, two-period, open-label trials that evaluated the effects of multiple doses of desvenlafaxine on the pharmacokinetics of desipramine, a cytochrome P450 (CYP) 2D6 enzyme substrate, are presented. Healthy individuals aged 18-45 years were administered a single oral dose of 50 mg desipramine with and without 100 mg daily (n=34) or 400 mg daily (n=23) desvenlafaxine for 5 days. After coadministration of 100 mg desvenlafaxine, desipramine exposure, measured by peak plasma concentration (C(max)) and total area under the plasma concentration-versus-time curve (AUC), showed minimal increases of 25 and 17%, respectively; coadministration of 400 mg desvenlafaxine resulted in a 52% increase in desipramine C(max) and a 90% increase in AUC. For the 100 mg dose, the geometric least squares mean ratios and 90% confidence intervals (CIs) for desipramine AUC (117%; 90% CI 110-125%), 2-hydroxydesipramine AUC (114%; 90% CI 110-119%), and C(max) (110%; 90% CI 104-116%) were all within the 80-125% interval, showing the bioequivalence for AUC between desipramine administered alone and in combination with 100 mg desvenlafaxine. These results indicate that desvenlafaxine is a relatively weak inhibitor of CYP2D6 and that desvenlafaxine 100 mg, twice the recommended therapeutic dose of 50 mg, is unlikely to cause drug-drug interactions with CYP2D6 substrates.
authors.affiliation: Pfizer Inc., formerly Wyeth Research, Collegeville, Pennsylvania 19426, USA. alice.nichols@pfizer.com
authors.forename: Alice I
authors.initials: AI
authors.lastname: Nichols
authors.forename: Madelyn
authors.initials: M
authors.lastname: Abell
authors.forename: Abell
authors.initials: A
authors.lastname: Madelyn
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Behrle
authors.forename: Glen
authors.initials: G
authors.lastname: Frick
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Paul
mesh_terms: D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001682:Biological Availability; D003511:Cyclohexanols / Q000008:administration & dosage / Q000009:adverse effects*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000069468:Desvenlafaxine Succinate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D050216:Metabolic Detoxication, Phase I; D008875:Middle Aged; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine; C028653:2-hydroxydesipramine; D000069468:Desvenlafaxine Succinate