Genomic and Sex Contributions to Interindividual Variability in Pitavastatin Bioavailability

This study investigates pharmacogenetic determinants of pitavastatin disposition using a candidate-gene approach.

In 48 healthy volunteers, 138 variants across 40 genes involved in drug metabolism and transport were analysed to assess their relationship with pitavastatin pharmacokinetics, alongside the influence of sex and biogeographical origin.

Women exhibited 35% higher AUC and C_max values than men; however, these differences disappeared after adjusting for the dose/weight (DW) ratio, with only a 22% increase in t_1/2 remaining. The most prominent finding was the 50%-65% increase in AUC/DW and C_max/DW observed in decreased function (DF) individuals compared with increased function (IF) and normal function (NF) carriers of SLCO1B1 phenotype, reinforcing its role as the primary hepatic uptake transporter for pitavastatin. Additional variants in efflux transporters such as ABCB1, ABCC3 and ABCG2 may also contribute to interindividual variability, albeit to a lesser extent. Among drug-metabolising enzymes, CYP4F2 emerged as a candidate for further investigation, given the 36% reduction in AUC_48h/DW associated with the rs3093200 variant. No significant associations were detected for CYP2D6 or CYP2C9 genes. Evidence to date does not indicate a meaningful impact of UGT enzymes on pitavastatin pharmacokinetics.

Overall, these findings highlight several genetic factors that may modulate pitavastatin disposition, warranting confirmation through functional studies or larger population cohorts.