SMARTc Unit, CRCM, Inserm U1068, Aix Marseille University, Marseille, France.
Clinical Biochemistry Department, Caremeau University Hospital of Nîmes, Nîmes, France.
Pharmacogenomics. 2020 Feb;21(3):173-179. doi: 10.2217/pgs-2019-0127.
A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 (-rs3832043) and nuclear receptor PXR (-rs3814055-rs2472677 and -rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting , genetic polymorphisms of have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.
一位 53 岁的女性患有甲状腺乳头状癌，接受了 800mg 索拉非尼治疗，迅速出现 3 级毒性。剂量逐步减少，数次停药至 200mg 每 2 天，但严重毒性仍持续存在。血浆药物监测显示即使在低剂量时也存在高暴露。然后将剂量进一步减少至 200mg 每 3 天，最终耐受可接受（即，1 级毒性），RECIST 成像显示疾病稳定。药物遗传学研究表明，影响 UGT1A9（-rs3832043）和核受体 PXR（-rs3814055-rs2472677 和 -rs10934498）的多态性，可能导致索拉非尼的肝代谢酶（即 CYP 和 UGT）下调。贝叶斯方法估计的患者清除率（0.48 l/h）明显低于通常描述的。这是首次发现，除了影响 的突变外，药物遗传学的多态性可能与索拉非尼摄入后的血浆过度暴露和严重毒性有关。
