Effect of Genetic Variants on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Involvement of ABCG2, SLCO1B1 and NAT2

Statins are the primary drugs used to prevent cardiovascular disease by inhibiting the HMG-CoA reductase, an enzyme crucial for the synthesis of LDL cholesterol in the liver. A significant number of patients experience adverse drug reactions (ADRs), particularly musculoskeletal problems, which can affect adherence to treatment. Recent clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2022, recommend adjusting rosuvastatin doses based on genetic variations in the <i>ABCG2</i> and <i>SLCO1B1</i> genes to minimize ADRs and improve treatment efficacy. Despite these adjustments, some patients still experience ADRs. So, we performed a candidate gene study to better understand the pharmacogenetics of rosuvastatin. This study included 119 healthy volunteers who participated in three bioequivalence trials of rosuvastatin alone or in combination with ezetimibe at the Clinical Trials Unit of the Hospital Universitario de La Princesa (UECHUP). Participants were genotyped using a custom OpenArray from ThermoFisher that assessed 124 variants in 38 genes associated with drug metabolism and transport. No significant differences were observed according to sex or biogeographic origin. A significant increase in t_1/2 (<i>p_multivariate</i>(<i>p_mv</i>) = 0.013) was observed in the rosuvastatin plus ezetimibe trial compared with the rosuvastatin alone trials. Genetic analysis showed that decreased (DF) and poor function (PF) volunteers for the ABCG2 transporter had higher AUC_∞/DW (adjusted dose/weight), AUC_72h/DW and C_max/DW compared to normal function (NF) volunteers (<i>p_mv</i>< 0.001). DF and PF volunteers for SLCO1B1 showed an increase in AUC_72h/DW (<i>p_mv</i> = 0.020) compared to increased (IF) and NF individuals. Results for ABCG2 and SLCO1B1 were consistent with the existing literature. In addition, AUC_∞/DW, AUC_72h/DW and C_max/DW were increased in intermediate (IA) and poor (PA) NAT2 acetylators (<i>p_mv</i> = 0.001, <i>p_mv</i>< 0.001, <i>p_mv</i>< 0.001, respectively) compared to rapid acetylators (RA), which could be associated through a secondary pathway that was previously unknown.