Impact ofSLCO1B1Genotype on Pediatric Simvastatin Acid Pharmacokinetics

This study investigated the impact of allelic variation inSLCO1B1, a gene encoding for the liver‐specific solute carrier organic anion transporter family member 1B1 protein (SLCO1B1), on simvastatin and simvastatin acid (SVA) systemic exposure in children and adolescents. Participants (8–20 years old) with at least 1 variantSLCO1B1c.521T>C allele (521TC, n = 15; 521CC, n = 2) and 2 wild‐type alleles (521TT, n = 15) completed a single oral dose pharmacokinetic study. At equivalent doses, SVA exposure was 6.3‐ and 2.5‐fold greater in 521CC and TC genotypes relative to 521TT (Cmax, 2.1 ± 0.2 vs 1.0 ± 0.5 vs 0.4 ± 0.3 ng/mL;P < .0001; and AUC, 12.1 ± 0.3 vs 4.5 ± 2.5 vs 1.9 ± 1.8 ng·h/mL;P < .0001). The impact of theSLCO1B1c.521 genotype was more pronounced in children, although considerable interindividual variability in SVA exposure was observed within genotype groups. In addition, SVA systemic exposure was negligible in 25% of pediatric participants. Further investigation of the ontogeny and genetic variation of SVA formation and SLCO1B1‐mediated hepatic uptake is necessary to better understand the variability in SVA exposure in children and its clinical consequences.