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.