Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care.
Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care.
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DOI：
10.1161/circgenetics.113.000099
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Kim RB
中科院分区：
文献类型：
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作者：
DeGorter MK;Tirona RG;Schwarz UI;Choi YH;Dresser GK;Suskin N;Myers K;Zou G;Iwuchukwu O;Wei WQ;Wilke RA;Hegele RA;Kim RB
他汀类药物治疗的一个障碍是与全身药物暴露增加相关的肌病。我们的目的是研究临床和药物遗传学变量与患者他汀类药物浓度之间的关系。在门诊转诊中心，总共前瞻性招募了299例服用阿托伐他汀或瑞舒伐他汀的患者。使用多元线性回归评估临床变量和转运蛋白基因多态性对他汀类药物浓度的影响。我们观察到服用相同剂量的患者中他汀类药物浓度的变化为45倍。校正性别、年龄、体重指数、种族、剂量和距末次给药的时间后，SLCO 1B 1 c.521 T> C（p <0.001）和ABCG 2 c.421 C> A（p <0.01）对瑞舒伐他汀浓度具有重要意义（最终模型校正R2 = 0.56）。阿托伐他汀浓度与SLCO 1B1 c.388A> G（p <0.01）和c.521T> C（p <0.05）以及4 β-羟基胆固醇（CYP3A活性标志物）相关（校正R2 = 0.47）。第二个队列的579例患者从初级和专科护理数据库进行了回顾性基因分型。在该队列中，与他汀类药物浓度相关的基因型在剂量组之间的分布没有差异，这意味着供应商尚未优化每个患者的风险-效益比。在常规实践中，接受最高剂量的患者中，预计近50%的他汀类药物浓度大于第90百分位数。患者他汀类药物暴露的个体间差异与摄取和外排转运蛋白多态性相关。结合基因组和临床变量，以避免高阿托伐他汀和瑞舒伐他汀水平的算法描述，进一步的研究将确定这种方法是否降低他汀类肌病的发生率。
A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for gender, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (p < 0.001) and ABCG2 c.421C>A (p < 0.01) were important to rosuvastatin concentration (adjusted R2 = 0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (p < 0.01) and c.521T>C (p < 0.05), and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2 = 0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine if this approach reduces incidence of statin-myopathy.