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Volume 16
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Article

Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron

by
Paula Soria-Chacartegui
1,
Patricia Cendoya-Ramiro
1,
Eva González-Iglesias
1,
Samuel Martín-Vílchez
1,
Andrea Rodríguez-Lopez
1,
Gina Mejía-Abril
1,
Manuel Román
1,
Sergio Luquero-Bueno
1,
Dolores Ochoa
1 and
Francisco Abad-Santos
1,2,*
1
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Faculty of Medicine, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain
2
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Pharmaceutics 2024, 16(8), 1077; https://doi.org/10.3390/pharmaceutics16081077
Submission received: 23 July 2024 / Revised: 13 August 2024 / Accepted: 15 August 2024 / Published: 17 August 2024
(This article belongs to the Special Issue Emerging Strategies in Drug Development and Clinical Care in the Era of Personalized and Precision Medicine, 2nd Edition)
Review Reports Versions Notes

Abstract

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics.
Keywords: mirabegron; pharmacogenetics; CYP2D6; overactive bladder; pharmacokinetics mirabegron; pharmacogenetics; CYP2D6; overactive bladder; pharmacokinetics

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MDPI and ACS Style

Soria-Chacartegui, P.; Cendoya-Ramiro, P.; González-Iglesias, E.; Martín-Vílchez, S.; Rodríguez-Lopez, A.; Mejía-Abril, G.; Román, M.; Luquero-Bueno, S.; Ochoa, D.; Abad-Santos, F. Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron. Pharmaceutics 2024, 16, 1077. https://doi.org/10.3390/pharmaceutics16081077

AMA Style

Soria-Chacartegui P, Cendoya-Ramiro P, González-Iglesias E, Martín-Vílchez S, Rodríguez-Lopez A, Mejía-Abril G, Román M, Luquero-Bueno S, Ochoa D, Abad-Santos F. Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron. Pharmaceutics. 2024; 16(8):1077. https://doi.org/10.3390/pharmaceutics16081077

Chicago/Turabian Style

Soria-Chacartegui, Paula, Patricia Cendoya-Ramiro, Eva González-Iglesias, Samuel Martín-Vílchez, Andrea Rodríguez-Lopez, Gina Mejía-Abril, Manuel Román, Sergio Luquero-Bueno, Dolores Ochoa, and Francisco Abad-Santos. 2024. "Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron" Pharmaceutics 16, no. 8: 1077. https://doi.org/10.3390/pharmaceutics16081077

APA Style

Soria-Chacartegui, P., Cendoya-Ramiro, P., González-Iglesias, E., Martín-Vílchez, S., Rodríguez-Lopez, A., Mejía-Abril, G., Román, M., Luquero-Bueno, S., Ochoa, D., & Abad-Santos, F. (2024). Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron. Pharmaceutics, 16(8), 1077. https://doi.org/10.3390/pharmaceutics16081077

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