An Investigational Study on the Role of CYP2D6, CYP3A4 and UGTs Genetic Variation on Fesoterodine Pharmacokinetics in Young Healthy Volunteers

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2024-09, Vol.17 (9), p.1236
• Main Authors: Rodríguez-Lopez, Andrea, Ochoa, Dolores, Soria-Chacartegui, Paula, Martín-Vilchez, Samuel, Navares-Gómez, Marcos, González-Iglesias, Eva, Luquero-Bueno, Sergio, Román, Manuel, Mejía-Abril, Gina, Abad-Santos, Francisco
• Format: Article
• Language: English
• Subjects: Analysis; Bioavailability; Biogeography; Bladder; Clinical trials; Constipation; CYP2D6; Drug dosages; Drug therapy; Dutasteride; Enzymes; Ethylenediaminetetraacetic acid; fesoterodine; Genetic aspects; Genetic polymorphisms; Genotype & phenotype; Metabolism; Metabolites; Patients; pharmacogenetics; Pharmacokinetics; Plasma; Side effects; Urinary incontinence; Volunteers; Women
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17091236

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (Cmax/DW)), elimination (terminal half-life (T1/2) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and Cmax/DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and Cmax/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, Cmax, and CL/F of 5-HMT, which should be confirmed in other studies.