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

<b><i>Introduction:</i></b> 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. <b><i>Materials and Methods:</i></b> 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. <b><i>Results:</i></b> An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (C_max/DW)), elimination (terminal half-life (T_1/2) 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 C_max/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 C_max/DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T_1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. <b><i>Conclusions:</i></b> 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 <i>UGT</i> family and AUC, C_max, and CL/F of 5-HMT, which should be confirmed in other studies.