An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects
| Autor: | Ron Pedersen, Penny Fatato, Christine J Guico-Pabia, Alice I. Nichols, Albena Patroneva, Jeffrey Paul, Jennifer A. Isler, Qin Jiang, Michael E. Burczynski, Sandra M. Connolly |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Adult
Male medicine.medical_specialty Pharmaceutical Science Thiophenes Duloxetine Hydrochloride Pharmacology chemistry.chemical_compound Pharmacokinetics Desvenlafaxine Succinate Desipramine Internal medicine medicine Humans Duloxetine Drug Interactions Biotransformation Cross-Over Studies business.industry Middle Aged Cyclohexanols Crossover study Antidepressive Agents Desvenlafaxine Endocrinology Cytochrome P-450 CYP2D6 chemistry Area Under Curve Female business Reuptake inhibitor medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 36:2484-2491 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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