Intrinsic Factors Influencing Simvastatin and Simvastatin Acid Pharmacokinetics: Age‐Related Studies in Thai Adults and Cross‐Population Comparisons

Intrinsic factors such as age and ethnicity influence statin pharmacokinetics (PK) and may increase the risk of muscle-related adverse events. This study investigated the effect of age on the PK of simvastatin (SV) and its active metabolite, simvastatin acid (SVA), in healthy Thai subjects using an LC-MS/MS assay while accounting for key SLCO1B1 variants known to affect statin exposure. We further compared our results with published data across multiple ethnic populations via meta-analysis and conducted an exploratory pharmacogenetic analysis of SVA disposition-related genes to identify potential candidate variants contributing to PK differences observed between Thai and Caucasian populations. The pharmacokinetic results showed that aging significantly increased SV C_max but did not alter SVA exposure, while SLCO1B1 decreased and poor functions were associated with higher SVA exposure. The meta-analysis revealed that Thai subjects showed significantly higher SVA levels than Caucasians, Chinese, and Japanese. The pharmacogenetic analysis identified functional or promoter variants in SLCO1B1 and PON genes with allele frequency differences directionally consistent with the observed PK differences between Thais and Caucasians. Our results may partly explain the higher incidence of SV-associated rhabdomyolysis previously reported in Thais compared with Caucasians and highlight the relevance of these intrinsic factors in SV and SVA PK, with implications for dosing considerations in Thai patients. Additional studies are warranted to further support the involvement of these polymorphic variants in the observed interethnic differences in SVA PK and adverse outcomes.