Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia.
Impact of SLCO1B1 Genetic Variation on Rosuvastatin Systemic Exposure in Pediatric Hypercholesterolemia.
复制标题
SLCO1B1 基因变异对小儿高胆固醇血症瑞舒伐他汀全身暴露的影响。
DOI：
10.1111/cts.12749
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Leeder,JSteven
中科院分区：
文献类型：
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作者：
Wagner,JonathanB;Abdel-Rahman,Susan;Gaedigk,Andrea;Gaedigk,Roger;Raghuveer,Geetha;Staggs,VincentS;VanHaandel,Leon;Leeder,JSteven
本研究探讨了SLCO 1B 1基因型对高胆固醇血症儿童和青少年中瑞舒伐他汀全身暴露的影响。具有至少一种SLCO 1B1c.521 T>C等位基因变体的参与者（8-21岁）（521 TC，n= 13; 521 CC，n= 2）和野生型对照（521 TT，n= 13）完成了单次口服剂量药代动力学研究。在我们的儿科队列中，SLCO 1B1c.521序列变异对瑞舒伐他汀（RVA）全身暴露量的贡献变异性与既往成人研究相当。与521 TT受试者相比，c.521TC和c.521CC基因型受试者0-24小时的RVA浓度-时间曲线（AUC 0 -24）分别高1.4倍和2.2倍。SLCO 1B 1基因型组内RVA暴露量的个体间变异性超过SLCO 1B 1基因型组观察到的平均RVA暴露量的约1.5倍至2倍差异，表明其他因素也导致瑞舒伐他汀剂量-暴露量关系的个体间变异性。进行的多变量模型证实，SLCO 1B1c.521 T>C基因型是该儿科队列中RVA全身暴露量的主要影响因素，约占RVA AUC 0 -24变异性的30%。然而，在迄今为止在儿科人群中研究的他汀类药物中，RVA的全身暴露变异性最低。
This study investigated the impact ofSLCO1B1genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8–21 years) with at least one allelic variant ofSLCO1B1c.521T>C (521TC,n= 13; 521CC,n= 2) and wild type controls (521TT,n= 13) completed a single oral dose pharmacokinetic study. The variability contributed bySLCO1B1c.521 sequence variation to rosuvastatin (RVA) systemic exposure among our pediatric cohort was comparable to previous studies in adults. RVA concentration‐time curve from 0–24 hours (AUC0–24) was 1.4‐fold and 2.2‐fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Interindividual variability of RVA exposure withinSLCO1B1genotype groups exceeded the ~ 1.5‐fold to 2‐fold difference in mean RVA exposure observed amongSLCO1B1genotype groups, suggesting that other factors also contribute to interindividual variability in the rosuvastatin dose‐exposure relationship. A multivariate model performed confirmedSLCO1B1c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~ 30% of the variability RVA AUC0–24. However, of the statins investigated to date in the pediatric population, RVA has the lowest magnitude of variability in systemic exposure.