desvenlafaxine-succinate and 2-hydroxydesipramine

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.

Topics: Adolescent; Adult; Antidepressive Agents; Antidepressive Agents, Tricyclic; Biological Availability; Cyclohexanols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Metabolic Detoxication, Phase I; Middle Aged; Neurotransmitter Uptake Inhibitors; Polymorphism, Genetic; Young Adult

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.

Topics: Adult; Antidepressive Agents; Area Under Curve; Cross-Over Studies; Cyclohexanols; Cytochrome P-450 CYP2D6 Inhibitors; Desipramine; Desvenlafaxine Succinate; Drug Interactions; Enzyme Inhibitors; Female; Genotype; Humans; Least-Squares Analysis; Male; Middle Aged; Paroxetine; United States; Young Adult

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.

Topics: Adult; Antidepressive Agents; Area Under Curve; Biotransformation; Cross-Over Studies; Cyclohexanols; Cytochrome P-450 CYP2D6; Desipramine; Desvenlafaxine Succinate; Drug Interactions; Duloxetine Hydrochloride; Female; Humans; Male; Middle Aged; Thiophenes