Crona D J, Ramirez J, Qiao W, de Graan A-J, Ratain M J, van Schaik R H N, Mathijssen R H J, Rosner G L, Innocenti F
University of North Carolina Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC, USA.
University of Chicago, Department of Medicine, Chicago, IL, USA.
Pharmacogenomics J. 2016 Feb;16(1):54-9. doi: 10.1038/tpj.2015.23. Epub 2015 Apr 14.
The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A128, UGT1A193 and SLCO1B11b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A128 and UGT1A193. In addition to UGT1A128, this study independently validated UGT1A193 and SLCO1B11b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.
本研究的总体目标是为先前与伊立替康所致中性粒细胞减少症及药代动力学相关的5个基因中的9种基因变异的临床有效性提供证据。在一个癌症患者发现队列中，对与绝对中性粒细胞计数（ANC）最低点和/或伊立替康药代动力学相关的变异进行基因分型，该队列中有108名癌症患者作为独立复制队列。患者每3周接受一次单药伊立替康治疗。对于ANC最低点，我们在单变量分析中复制了UGT1A128、UGT1A193和SLCO1B11b。对于伊立替康浓度-时间曲线下面积（AUC0-24），我们复制了ABCC2 -24C>T；然而，ABCC2 -24C>T仅预测了一小部分变异。对于SN-38 AUC0-24和葡萄糖醛酸化率，我们复制了UGT1A128和UGT1A193。除UGT1A128外，本研究还独立验证了UGT1A193和SLCO1B11b作为伊立替康所致中性粒细胞减少症的新预测指标。进一步证明它们的临床效用将优化癌症患者的伊立替康治疗。
