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

Frontiers in Pharmacology

Pharmacology

Sofía Calleja¹  Marcos Navares-Gómez¹  Alejandro de Miguel¹  Gonzalo Villapalos-García¹  Dolores Ochoa¹  Samuel Martín-Vílchez¹  Manuel Román¹  Gina Mejia-Abril¹  Paula Soria-Chacartegui¹  Francisco Abad-Santos²  Pablo Zubiaur³ 

[1] Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain;Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain;Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain;Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children’s Mercy Research Institute, Kansas City, MO, United States;

关键词: desvenlafaxine;    pharmacogenetics;    major depressive disorder;    precision medicine;    pharmacokinetics;    safety;   

DOI  :  10.3389/fphar.2023.1110460

 received in 2022-11-28, accepted in 2023-01-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

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., CYP enzymes like CYP2D6, CYP3A4, or CYP2C19; ABC transporters like ABCB1; SLCO1B1; and UGT enzymes like UGT1A1) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials (n = 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, p = 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.

【 授权许可】

Unknown   
Copyright © 2023 Calleja, Zubiaur, Ochoa, Villapalos-García, Mejia-Abril, Soria-Chacartegui, Navares-Gómez, de Miguel, Román, Martín-Vílchez and Abad-Santos.