An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

Abstract

ABSTRACT: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.Concomitant use of a drug that affects the activity of the same cytochrome P450 (P450) enzyme system responsible for biotransformation of another drug can lead to significant elevations in plasma concentration and potentially important drug-drug interactions (Preskorn and Flockhart, 2004). Such interactions may be associated with poor tolerability or increased risk for toxicity. In addition, for drugs requiring biotransformation via P450 enzymes from an inactive/less active parent compound to a pharmacologically active metabolite, drug interactions may manifest as a reduction in efficacy (Stearns et al., 2003;Preskorn and Flockhart, 2004;Preskorn and Werder, 2006). Drug interactions have an impact on clinical care and may create the need for dose adjustments, consideration of different therapeutic options, or other management strategies.Several antidepressants are known to inhibit CYP2D6 activity (Zanger et al., 2004). The selective serotonin reuptake inhibitors are associated with varying degrees of CYP2D6 inhibition. For example, paroxetine and fluoxetine strongly inhibit CYP2D6 (K i of 2.0 and 3.0 ...

Assessing Risks and Benefits of Nonhormonal Treatments for Vasomotor Symptoms in Perimenopausal and Postmenopausal Women

“…80 In vitro data indicate that desvenlafaxine has negligible effect on CYP450 enzymes or on p-glycoprotein activity and, consequently, is believed to have a minimal likelihood of inducing drug interactions. [89][90][91] Gabapentin. Gabapentin is a c-aminobutyric acid analogue indicated for the treatment of partial seizures and postherpetic neuralgia.…”

Desvenlafaxine in the treatment of major depressive disorder

“…To examine the clinical implications, the effects of DVS 100 mg and duloxetine 30 mg bid on plasma levels of desipramine were compared in healthy subjects in a randomized, open label, crossover study. 29 In comparison to desipramine alone, co-administration of duloxetine resulted in increases in AUC and C max of desipramine (122% and 63% respectively). These were signifi cantly greater than the increases observed with DVS co-administration (22% and 19%, respectively), suggesting that DVS is not a clinically signifi cant inhibitor of CYP2D6 activity.…”

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

“…Phase I hepatic metabolism of desvenlafaxine appears to play a small role in its elimination, marked by metabolism to N,O-didesmethylvenlafaxine by the cytochrome P450 (CYP450) 3A4 pathway [5]. Because desvenlafaxine is primarily metabolized via glucuronidation, and clinical reports have shown that desvenlafaxine exerts minimal effects on the activities of the CYP450 enzymes or p-glycoprotein, the potential ability of other drugs to alter desvenlafaxine metabolism is low [6][7][8][9][10].…”