Comparison of the Pharmacokinetics of Venlafaxine Extended Release and Desvenlafaxine in Extensive and Poor Cytochrome P450 2D6 Metabolizers

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 ...

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“…These data support prior findings suggesting that desvenlafaxine is not a substantial inhibitor of CYP2D6 activity (Preskorn et al, 2007b). …”

Section: Effects Of Desvenlafaxine Vs Duloxetine On Desipramine Pksupporting

confidence: 82%

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

Patroneva¹,

Connolly²,

Fatato³

et al. 2008

Drug Metab Dispos

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“…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].…”

Section: Introductionmentioning

confidence: 99%

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

Nichols¹,

Richards²,

Behrle³

et al. 2012

JBB

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“…121 In contrast with desvenlafaxine, the CYP2D6 genetic polymorphism has a significant influence on venlafaxine pharmacokinetics. 122 Both drugs may have low potential for drug interactions, because of low protein binding and a relatively weak inhibitory effect on CYP isoenzymes. 90,123 Nevertheless, increased plasma levels of imipramine, its metabolite desimipramine, 124 and risperidone were associated with concomitant administration of venlafaxine.…”

Section: 152mentioning

confidence: 99%

“…120 Desvenlafaxine is further metabolized by CYP3A4. 122 Other metabolic pathways for venlafaxine include N-demethylation which is probably mediated by CYP3A4.…”

Section: 152mentioning

confidence: 99%

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Getting the balance right: Established and emerging therapies for major depressive disorders

Perović

Jovanović²,

Miljković³

et al. 2010

NDT

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Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.

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Comparison of the Pharmacokinetics of Venlafaxine Extended Release and Desvenlafaxine in Extensive and Poor Cytochrome P450 2D6 Metabolizers

Cited by 72 publications

References 9 publications

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

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

Effect of Food on the Pharmacokinetics of Desvenlafaxine in Healthy Subjects

Getting the balance right: Established and emerging therapies for major depressive disorders

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