Aging significantly increased simvastatin Cmax but did not alter simvastatin acid exposure, while Thai subjects showed significantly higher simvastatin acid levels than Caucasians, Chinese, and Japanese, with SLCO1B1 and PON gene variants potentially contributing to these interethnic pharmacokinetic differences.
Key Findings
Results
Aging significantly increased simvastatin Cmax but did not alter simvastatin acid exposure in healthy Thai subjects.
The study used an LC-MS/MS assay to measure pharmacokinetics of simvastatin (SV) and its active metabolite simvastatin acid (SVA) in healthy Thai subjects.
Age was found to significantly increase SV Cmax.
SVA exposure (area under the curve) was not significantly altered by age.
The study accounted for key SLCO1B1 variants known to affect statin exposure.
Results
SLCO1B1 decreased and poor function variants were associated with higher simvastatin acid exposure.
SLCO1B1 variants with decreased and poor function were associated with higher SVA exposure.
SLCO1B1 encodes the organic anion transporting polypeptide 1B1 (OATP1B1), which mediates hepatic uptake of statins.
This finding is consistent with the known role of SLCO1B1 in statin disposition.
The pharmacogenetic analysis specifically examined SLCO1B1 variants as key factors affecting statin PK.
Results
Thai subjects showed significantly higher simvastatin acid levels compared to Caucasian, Chinese, and Japanese populations in a meta-analysis.
A meta-analysis was conducted comparing results with published data across multiple ethnic populations.
Thai subjects had significantly higher SVA levels than Caucasians, Chinese, and Japanese populations.
The meta-analysis included cross-population comparisons of simvastatin pharmacokinetics.
The finding of higher SVA exposure in Thais may partly explain the higher incidence of simvastatin-associated rhabdomyolysis previously reported in Thais compared with Caucasians.
Results
Functional or promoter variants in SLCO1B1 and PON genes showed allele frequency differences between Thai and Caucasian populations directionally consistent with observed pharmacokinetic differences.
An exploratory pharmacogenetic analysis of SVA disposition-related genes was conducted to identify potential candidate variants.
Both SLCO1B1 and PON (paraoxonase) gene variants were identified with allele frequency differences between Thais and Caucasians.
The allele frequency differences were directionally consistent with the observed PK differences between the two populations.
These variants were identified as potential candidate variants contributing to the interethnic PK differences observed between Thai and Caucasian populations.
Discussion
Higher simvastatin acid exposure in Thai patients may partly explain the higher incidence of simvastatin-associated rhabdomyolysis previously reported in Thais compared with Caucasians.
The authors link the pharmacokinetic findings to clinical safety outcomes, specifically rhabdomyolysis.
The higher SVA levels observed in Thais compared to other ethnic groups are proposed as a mechanistic explanation for greater muscle toxicity risk.
The findings highlight the relevance of intrinsic factors (age and ethnicity) in SV and SVA PK, with implications for dosing considerations in Thai patients.
Additional studies are noted as warranted to further support the involvement of polymorphic variants in the observed interethnic differences in SVA PK and adverse outcomes.
Background
The study investigated age and ethnicity as intrinsic factors influencing simvastatin pharmacokinetics and muscle-related adverse event risk.
Intrinsic factors such as age and ethnicity were identified as factors influencing statin pharmacokinetics and potentially increasing the risk of muscle-related adverse events.
Healthy Thai subjects were enrolled as study participants.
LC-MS/MS (liquid chromatography-tandem mass spectrometry) was used as the analytical assay.
Both a primary PK study in Thai adults and a meta-analysis of cross-population data were conducted.