Impact of Pharmacokinetic Gene Polymorphisms on Statin-Induced Myotoxicity in Thai Patients Treated With Simvastatin

Statin-induced myotoxicity (SIM) is a common adverse effect of simvastatin therapy, which can negatively impact patient adherence and treatment outcomes. This study aims to investigate the impacts of pharmacokinetic (PK) gene polymorphisms on SIM in Thai population treated with simvastatin. One hundred forty-eight Thai participants, including 23 with SIM and 125 tolerant controls were enrolled. The pharmacokinetic genes including, ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, CYP3A4, and CYP3A5, were genotyped using MassARRAY System. Significant associations were identified for C allele of SLCO1B1 rs4149056 (c.521T>C) (OR = 1.9; 95% CI: 1.1-3.5; p = 0.02) and T allele of ABCC2 rs717620 (-24C>T) (OR = 2.2; 95% CI = 1.1-4.4; p = 0.02). Haplotype analysis of SLCO1B1 c.521T>C and c.388A>G revealed that the *15 haplotype (c.521C and c.388G) was significantly associated with SIM, with a higher frequency in SIM cases (13.0%) compared to controls (6.0%) (OR 2.8; 95% CI = 1.3-6.0; p < 0.01). Furthermore, the decreased function phenotype of OATP1B1 (SLCO1B1*1b/*5 or *1b/*15), was associated with SIM compared to normal function phenotype. Notably, patients with the decreased function phenotype using simvastatin 20-40 mg/day had a substanstially increase risk of SIM (OR = 10.0; 95% CI = 1.6-63.4; p = 0.02). These findings highlight the influence of PK gene polymorphisms on SIM risk and support the importance of genotype-guided simvastatin therapy to minimize adverse effects and improve patient care. Moreover, these also reinforce current CPIC guidelines, which recommend adjusting statins, including simvastatin, therapy based on SLCO1B1 genotype to reduce the risk of myopathy.