Allegra Sarah, Di Paolo Antonello, Cusato Jessica, Fatiguso Giovanna, Arrigoni Elena, Danesi Romano, Corcione Silvia, DʼAvolio Antonio
Department of Medical Sciences, University of Turin-ASL "Città di Torino," Laboratory of Clinical Pharmacology and Pharmacogenetics Padiglione Q, Amedeo di Savoia Hospital, Turin, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Ther Drug Monit. 2018 Oct;40(5):602-609. doi: 10.1097/FTD.0000000000000536.
Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients.
Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time-concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach.
A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19 L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 versus 5.45 hours and 37.43 versus 46.71 L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared with individuals carrying at least one c.3435T allele with respect to methicillin-sensitive S. aureus, methicillin-resistant S. aureus, and Streptococcus pneumoniae species.
The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up therapeutic drug monitoring.
多种因素导致患者体内利奈唑胺血浆暴露量高度可变。最近，有人提出利奈唑胺可能是ABCB1的底物。因此，本临床研究旨在调查ABCB1基因多态性是否可预测27例危重症患者的利奈唑胺药代动力学。
通过实时聚合酶链反应等位基因鉴别系统评估基因型，并采用非线性混合效应建模方法分析利奈唑胺血浆浓度，包括谷浓度（Ctrough）和时间-浓度曲线下面积（AUC）。
发现abcb1 c.3435C>T基因多态性对利奈唑胺清除率有显著影响，野生型纯合子的清除率为13.19 L/h，其余个体为7.82 L/h。尽管个体间差异较大（60.8%），但这种差异具有统计学意义。c.3435CC和c.3435CT/TT患者的终末半衰期和分布容积值有显著差异（分别为2.78小时对5.45小时和37.43 L对46.71 L）。相反，基于c.3435C>T基因型的AUC和Ctrough差异观察到适度趋势。根据最终模型进行的模拟显示，对于甲氧西林敏感金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌和肺炎链球菌，.3435CC个体的AUC/MIC参数累积反应分数优于携带至少一个c.3435T等位基因的个体。
所得结果表明ABCB1可能对利奈唑胺药代动力学有影响，这为抗菌化疗中的药物遗传学分析带来了新的兴趣。这些分析可纳入精准医学的治疗方案，包括联合使用基因评估（用于起始剂量）和后续治疗药物监测。
