Desvenlafaxine for major depressive disorder: incremental clinical benefits from a second-generation serotonin–norepinephrine reuptake inhibitor

Abstract

incremental benefits with desvenlafaxine, derived from straight-forward dosing, a simple metabolic profile and lack of interaction with active transporter P-gp and CYP enzymes may contribute to more consistent response, good tolerability and lower incidence of drug-drug interactions with concomitant medications.

Metabolites: novel therapeutics or “me-too” drugs? Using desvenlafaxine as an example

“…Pharmacokinetically, we should again cite the work of Nichols et al, 4,8 and observe the ratios of desvenlafaxine to venlafaxine after metabolism (DES/VEN ratio). Efficient metabolizers taking 75 mg of venlafaxine developed a DES/VEN ratio of 6.2, where poor metabolizers were approximately 50% less with a 3.3 ratio.…”

“…For example, there would not be competition for absorption in the medically ill MDD patient who is simultaneously taking other P-gp inducers or substrates, such as nelfinavir, amprenavir, saquinavir, digoxin, verapamil, ketoconazole, quinidine, talinolol, dexamethasone, cyclosporine, St. John's Wort, sertraline, paroxetine, citalopram, amitriptyline, nortriptyline, etc., thus allowing better drug plasma levels and chance of antidepressant response. 7,8 Summarizing, there should be a distinct minority of patients for whom the metabolite antidepressant desvenlafaxine is safer and better tolerated. This editorial could end with a simple, data-driven answer: desvenlafaxine should be used only in those patients who (a) are sensitive to nausea-based side effects (up to 8% per venlafaxine ER clinical trials outlined in its FDA package insert), (b) have clear CYP450 2D6-poor metabolizer status (10% of Caucasians 9 ), or (c) are P-gp efficient with more C alleles of the human MDR1 gene, allowing less transport of the drug from gut to liver and liver to systemic circulation (40% of Caucasians 10 ).…”

“…A better profile may exist for the desvenlafaxine metabolite, as it is not a P-gp substrate and may be more easily absorbed. For example, there would not be competition for absorption in the medically ill MDD patient who is simultaneously taking other P-gp inducers or substrates, such as nelfinavir, amprenavir, saquinavir, digoxin, verapamil, ketoconazole, quinidine, talinolol, dexamethasone, cyclosporine, St. John's Wort, sertraline, paroxetine, citalopram, amitriptyline, nortriptyline, etc., thus allowing better drug plasma levels and chance of antidepressant response 7 , 8 …”

A novel prodrug strategy to improve the oral absorption of O-desmethylvenlafaxine

“…O-desmethylvenlafaxine (ODV), also known as desvenlafaxine succinate, is a synthetic form of the major active metabolite of venlafaxine with antidepressant activity similar to that of venlafaxine but with a longer half-life (9,10). Compared with venlafaxine, direct intake of ODV for the treatment of diseases of the central nervous system has the advantages of being a single compound that is conducive to dosing adjustments and reducing the risk of interactions with other drugs (11)(12)(13)(14)(15). However, ODV contains a more exposed hydroxy group compared with venlafaxine, and therefore it has increased hydrophilicity, resulting in lower oral bioavailability.…”

Influence of combinations of drugs that act on the CYP2D6 metabolic pathway in the treatment of major depressive disorder: A population-based study

“…The reasons for the modest treatment success rates include inadequate doses, low patient compliance and intolerance due to adverse effects, especially when there is a high risk of drug interactions [35]. Additionally, there are individual differences in drug efficacy and tolerability which may be due to age, concomitant diseases, drug interactions and genetic polymorphisms of the drug-metabolizing enzymes [13,41].…”