Department of Medical Oncology, National Cancer Centre, National University of Singapore, Singapore.
Pharmacogenet Genomics. 2011 Nov;21(11):760-8. doi: 10.1097/FPC.0b013e32834a8639.
Vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer.
Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes.
Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele.
UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat, and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen.
伏立诺他是一种组蛋白去乙酰化酶抑制剂，目前正在实体瘤中进行积极评估，其代谢物由 UGT2B17 产生。体外研究表明，UGT2B17 无效基因型（UGT2B17*2）可降低 UGT2B17 的活性。这种变体在亚洲人中很常见，但在白种人中很少见，我们在亚洲转移性乳腺癌患者的临床研究中研究了它对伏立诺他药代动力学和药效学的影响。
符合条件的患者在先导 I 期接受 400 mg 伏立诺他单药治疗，随后进行 II 期研究。对患者进行 UGT2B17*2 基因分型，其与伏立诺他的药代动力学和临床结果相关。
26 例患者接受治疗，无完全缓解，1 例部分缓解，6 例持续 12 周或更长时间的稳定疾病，19 例进展性疾病。16 例（62%）患者为 UGT2B17*2 纯合子，伏立诺他-O-葡糖苷酸/伏立诺他的平均 AUC 比值明显较低（第 1 天分别为 1.84 和 2.51，P=0.02；第 15 天分别为 1.63 和 2.38，P=0.028），且 AUC 趋势较高（399.02 比 318.40，P=0.188），更严重的不良事件（31%比 0%，P=0.121），更高的临床获益率（40%比 10%，P=0.179），以及更长的中位无进展生存期（3.0 比 1.5 个月，P=0.087）。
UGT2B17*2 基因型降低了伏立诺他的葡萄糖醛酸化，可能增加了伏立诺他的疗效和毒性。这些观察结果对伏立诺他的开发很重要，并且可能对其他癌症和非癌症药物（如依西美坦和布洛芬）具有临床意义，这些药物也是 UGT2B17 的底物。
