The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis

Abstract

Background The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. Methods The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. Results Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. Conclusions CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

<p>In Vitro and In Vivo Rat Model Assessments of the Effects of Vonoprazan on the Pharmacokinetics of Venlafaxine</p>

“…ODV is considered to have an antidepressant effect similar to that of VEN. 22,23 CYP2D6 is an enzyme with high affinity and low volume, which dominates the VEN metabolism; 17 its activity is considered to be a major intrinsic factor in the pharmacokinetics of VEN, 11 but it is speculated that the clinical significance of altering the activity of CYP2D6 is limited. 24 Both vonoprazan and VEN are substrates of CYP2D6.…”

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression

“…Our findings are consistent with the results of previous PK studies that have reported altered plasma levels of VEN among different CYP2D6 metabolizers. 12,[31][32][33][34][35][36] However, in studies that reported O-desmethylvenlafaxine exposure, younger individuals with lower CYP2D6 activity also had lower O-desmethylvenlafaxine exposure. 32,34 By contrast, in our study of older adults, no Notably, all metabolizer groups had a wide variety range of Odesmethylvenlafaxine exposure at both lower dosages and higher dosages (Figures 2, 3).…”

“…Correspondingly, in these previous studies, there were no differences in active moiety concentrations between different groups of CYP2D6 metabolizers and we observed significantly higher active moiety exposure in CYP2D6 PMs. 12,37,38 The discrepancies of findings may come from differences in methods to classify CYP2D6 metabolizers. Some studies simply use VEN/Odesmethylvenlafaxine level ratio instead of determining CYP2D6 metabolizer status based on genotyping results.…”

“…11 Compared with CYP2D6 NMs, people with decreased CYP2D6 enzymatic activities have been showed to have altered VEN-related PK parameters, including maximum serum concentration and exposure (measured as area under the plot of plasma concentration of a drug vs. time), which may result in more adverse effects and reduced treatment adherence. 12 For these reasons, the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends avoiding VEN in CYP2D6 PMs. 13 Population PK modeling is a statistical method modeling individual key PK parameters as random effects to account for interindividual variability, as well as incorporating covariates (e.g., age, weight, and genetics) that may influence drug exposure.…”

Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication

“…A number of studies have indicated significant intra- and inter-individual pharmacokinetic variability for VEN and ODV. The influences of sex, age, gene polymorphism (CYP2D6, CYP2C19) and comedications (e.g., valproic acid, doxepin, trimipramine, quetiapine) have been previously reported ( Klamerus et al, 1996 ; McAlpine et al, 2011 ; Paulzen et al, 2018a ; Paulzen et al, 2018b ; Lin et al, 2018 ; Kowalewski et al, 2019 ; Wang et al, 2020 ). However, studies exploring these effects on dose and concentration have shown inconsistent results and mixed effects.…”