Impacts of Pharmacokinetic Gene Polymorphisms on Steady-State Plasma Concentrations of Simvastatin in Thai Population

Abstract

Simvastatin, an HMG-CoA reductase inhibitor, is widely used for hypercholesterolemia but may cause myotoxicity linked to its plasma concentration. Pharmacokinetic gene polymorphisms influence inter-individual variability in simvastatin exposure. This study investigated the effects of pharmacokinetic gene polymorphisms on steady-state simvastatin plasma levels in Thai patients. Eighty-nine Thai patients with dyslipidemia or coronary artery disease on simvastatin treatment for at least 2 weeks without dose adjustment were recruited from King Chulalongkorn Memorial Hospital. Simvastatin lactone and acid concentrations were measured 12 h post-dose using UHPLC–MS/MS. Pharmacokinetic gene polymorphisms, including ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, CYP3A4, and CYP3A5, were genotyped by MassARRAY System. The results showed that patients with the SLCO1B1 c.521TC+CC genotype had significantly higher simvastatin acid levels than those with c.521TT (0.53 vs. 0.19 ng/mL, p = 0.03). Similarly, the SLCO1B1*1b/*15 genotype was associated with higher simvastatin acid levels than SLCO1B1*1a/*1a (0.58 vs. 0.16 ng/mL, p < 0.001). These findings suggest that SLCO1B1 c.521T>C, alone or with c.388A>G (SLCO1B1*1b/*15), reduces OATP1B1 function, leading to elevated simvastatin acid levels and increased myotoxicity risk. This study confirms the association of SLCO1B1 rs4149056 (c.521T>C) with higher simvastatin plasma levels in Thai patients. The study highlights the potential role of SLCO1B1 genotyping, particularly rs4149056 (c.521T>C) and rs2306283 (c.388A>G), in guiding statin therapy for Thai patients, which could help optimize treatment and reduce adverse effects such as statin-induced myotoxicity.