Effects of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults

• Published in: International clinical psychopharmacology Vol. 28; no. 2; p. 99
• Main Authors: Nichols, Alice I, Abell, Madelyn, Madelyn, Abell, Chen, Yang, Behrle, Jessica A, Frick, Glen, Paul, Jeffrey
• Format: Journal Article
• Language: English
• Published: England 01.03.2013
• Subjects: Adolescent; Adult; Antidepressive Agents - administration & dosage; Antidepressive Agents - adverse effects; Antidepressive Agents, Tricyclic - adverse effects; Antidepressive Agents, Tricyclic - blood; Antidepressive Agents, Tricyclic - pharmacokinetics; Antidepressive Agents, Tricyclic - urine; Biological Availability; Cyclohexanols - administration & dosage; Cyclohexanols - adverse effects; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine - adverse effects; Desipramine - analogs & derivatives; Desipramine - blood; Desipramine - pharmacokinetics; Desipramine - urine; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Metabolic Detoxication, Phase I; Middle Aged; Neurotransmitter Uptake Inhibitors - administration & dosage; Neurotransmitter Uptake Inhibitors - adverse effects; Polymorphism, Genetic; Young Adult
• ISSN: 1473-5857
• DOI: 10.1097/YIC.0b013e32835c1f49

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.