对 AIDS 临床试验组方案 A5202 中阿扎那韦药代动力学和高胆红素血症的全基因组关联研究。
Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
机构信息
aDepartment of Medicine bDepartments of Pharmacology, Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee cThe Center for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester dTranslational Pharmacology Research Core, University at Buffalo, SUNY, Buffalo, New York eDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania fDepartment of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA gDepartment of Life Sciences, The Swiss Institute of Technology hDepartment of Microbiology, University Hospital, University of Lausanne, Lausanne, Switzerland.
出版信息
Pharmacogenet Genomics. 2014 Apr;24(4):195-203. doi: 10.1097/FPC.0000000000000034.
BACKGROUND
Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
METHODS
Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available.
RESULTS
Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance.
CONCLUSION
Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.
背景
阿扎那韦相关高胆红素血症可导致阿扎那韦提前停药和避免初始处方。我们使用全基因组基因分型和临床数据来描述 AIDS 临床试验组协议 A5202 中阿扎那韦药代动力学和高胆红素血症的决定因素。
方法
将 HIV-1 感染患者随机分配至含阿扎那韦/利托那韦的方案，对其血浆阿扎那韦药代动力学和间接胆红素浓度进行了特征描述。部分患者有全基因组基因型数据。
结果
542 名参与者的全基因组检测数据可用，其中 475 名参与者还具有关于阿扎那韦估计清除率和相关协变量的数据。443 名参与者的峰胆红素浓度和相关协变量可用。通过多变量分析，发现治疗过程中胆红素浓度峰值较高与 UGT1A1 rs887829 T 等位基因（P=6.4×10(-12)）、较高的基线血红蛋白水平（P=4.9×10(-13)）、较高的基线胆红素水平（P=6.7×10(-12)）和较慢的血浆阿扎那韦清除率（P=8.6×10(-11)）有关。对于胆红素峰浓度大于 3.0mg/dl 的患者，基线胆红素水平为 0.5mg/dl 或更高且血红蛋白浓度为 14g/dl 或更高时，阳性预测值为 0.51，当 rs887829 TT 纯合子时，其增加至 0.85。对于胆红素峰浓度为 3.0mg/dl 或更低的患者，当基线胆红素水平小于 0.5mg/dl 且血红蛋白浓度小于 14g/dl 时，阳性预测值为 0.91，当 rs887829 CC 纯合子时，其增加至 0.96。没有任何多态性在全基因组范围内预测阿扎那韦的药代动力学。
结论
阿扎那韦相关高胆红素血症最好通过考虑 UGT1A1 基因型、基线胆红素水平和基线血红蛋白水平来预测。作为药代动力学增强剂使用利托那韦可能会消除与阿扎那韦药代动力学相关的遗传关联。
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