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Key Differences Between Venlafaxine XR and Desvenlafaxine: An Analysis of Pharmacokinetic and Clinical Data
Clinical Pharmacy Specialist
Birmingham VA Medical Center
Venlafaxine XR and its major active metabolite, desvenlafaxine, are serotonin-norepinephrine reuptake inhibitors. Both are FDA-approved for the treatment of major depressive disorder and have essentially the same pharmacologic and pharmacokinetic profiles; however, the recommended dosing is notably different. The FDA approved recommended starting and maintenance dose for desvenlafaxine is 50 mg daily, while venlafaxine XR requires titration from 37.5 mg daily to the maintenance dose of 150 - 225 mg daily. The dose recommendation for desvenlafaxine is based on results from 8-week acute-phase clinical trials, but complete therapeutic response is not always achieved in this short time period. Venlafaxine XR relies on CYP2D6 for conversion to desvenlafaxine while desvenlafaxine has no significant metabolism by CYP2D6 at recommended doses. Both venlafaxine XR and desvenlafaxine have limited clinically significant drug interactions. The most striking difference between the two products is cost.
Venlafaxine extended release (XR) was the first once daily serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD) by the Food and Drug Administration (FDA) in 1997. 1 Approximately ten years later desvenlafaxine (O-desmethylvenlafaxine), the primary major active metabolite of venlafaxine, also joined the market for this indication in the form of desvenlafaxine succinate (Pristiq ® ). 2 The FDA also recently approved generic desvenlafaxine fumarate and the free base form of desvenlafaxine as both a generic and brand name (Khedezla ER) products. 3-5 This review will focus on desvenlafaxine succinate as efficacy, pharmacokinetic, and safety data are mostly available for this product.
Venlafaxine and desvenlafaxine are essentially pharmacologically equivalent. 6,10 Both are potent and selective inhibitors at serotonin and norepinephrine transporters with small differences in binding affinity measured by Ki value (lower Ki value indicates more selective binding). 2,6-8 The Ki values for serotonin reuptake pumps are 40.2 nM and 82 nM for desvenlafaxine and venlafaxine, respectively. 7,8 Ki values for norepinephrine reuptake pumps are 558.4 nM and 2480 nM for desvenlafaxine and venlafaxine, respectively. 7,8 Theoretically, higher binding affinity for desvenlafaxine versus venlafaxine at norepinephrine reuptake pumps could translate into differences in efficacy but this has not been validated in head-to-head clinical trials. Neither agent has significant affinity for cholinergic, alpha-adrenergic, or histaminergic receptors. 2,6 No clinically significant differences in adverse effects or tolerability have been identified in clinical trials. A detailed comparison of adverse effects and tolerability among SNRIs was recently published by Alipour. 9
While there may be subtle variances in receptor binding affinity and adverse effects, more notable differences between the two medications are related to metabolism and FDA approved dosage. 2,6 Because venlafaxine is primarily metabolized by cytochrome P450 (CYP) 2D6, there is concern that alterations in CYP2D6 activity could negatively impact efficacy and tolerability. 6 For this reason, it has been speculated that desvenlafaxine may be preferred in patients with drug-drug interactions and genetic polymorphisms which affect CYP2D6. 11-17 Furthermore, the fact that desvenlafaxine has the same starting and maintenance dose while venlafaxine XR should be gradually titrated may make desvenlafaxine a more appealing choice for some providers and patients. 2,6 The clinical impact of these differences has not been fully described. This article will review the data related to differences in metabolism and dosing between venlafaxine XR and desvenlafaxine to describe clinical significance.
At least 92% of a single dose of venlafaxine XR is absorbed and subsequently undergoes presystemic hepatic metabolism. It is estimated that 55% of a single dose is converted to desvenlafaxine via CYP2D6-mediated phase I oxidative metabolism. CYP1A2, CYP3A4, and CYP2C19 are responsible for the formation of other minor inactive oxidative metabolites including N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. 6 Unlike venlafaxine, desvenlafaxine is primarily inactivated via phase II glucuronidation with minimal oxidative metabolism via CYP3A4 to N,O-didesmethylvenlafaxine. 2 Both venlafaxine XR and desvenlafaxine are primarily renally eliminated as varying concentrations of unchanged drug, active, and inactive metabolites. 2,6 Because venlafaxine XR relies on CYP2D6 for conversion to the major active metabolite, there has been much investigation of the differences in its pharmacokinetic parameters and clinical efficacy among patients with CYP2D6 polymorphisms (polymorphisms in the CYP2D6 gene can result in phenotypes with varying levels of metabolic activity). 6 Extensive (EM) and intermediate metabolizers (IM) are considered to have ‘normal’ levels of enzyme activity while ultrarapid (UM) and poor metabolizers (PM) have significantly increased or decreased levels of enzyme activity, respectively. 18 While the majority of the population are EMs, up to 7% of Caucasians are CYP2D6 PMs. 19 Some have concluded that desvenlafaxine may be preferred in this population since it does not require CYP2D6 for clinical activity or clearance unlike many other antidepressants including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, duloxetine, and venlafaxine. 11,13,16