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

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 (t_1/2) (univariate p-value (p_uv) = 0.018) and incidence of adverse reactions (ADRs) (p_uv = 0.008, multivariate p (p_mv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t_1/2 than the T/T genotype (p_uv = 0.002, p_mv = 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 (p_uv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (p_uv = 0.007, p_mv = 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.