Impact of polymorphisms in CYP and UGT enzymes and ABC and SLCO1B1 transporters on the pharmacokinetics and safety of desvenlafaxine

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study...

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Published in:Frontiers in pharmacology 2023-02, Vol.14, p.1110460-1110460
Main Authors: Calleja, Sofía, Zubiaur, Pablo, Ochoa, Dolores, Villapalos-García, Gonzalo, Mejia-Abril, Gina, Soria-Chacartegui, Paula, Navares-Gómez, Marcos, de Miguel, Alejandro, Román, Manuel, Martín-Vílchez, Samuel, Abad-Santos, Francisco
Format: Article
Language:English
Subjects:
desvenlafaxine
major depressive disorder
pharmacogenetics
pharmacokinetics
Pharmacology
precision medicine
safety
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Summary:Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., enzymes like , , or ; transporters like ; ; and enzymes like ) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials ( = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2023.1110460