Department of Pharmacy, Shiga University of Medical Science Hospital, Seta Tsukinowacho, Otsu City, Shiga, 520-2192, Japan.
Cancer Chemother Pharmacol. 2013 Jul;72(1):269-72. doi: 10.1007/s00280-013-2187-9. Epub 2013 May 15.
Sorafenib is primarily metabolized in the liver, by CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation. However, there is little information about the pharmacokinetic interaction of sorafenib. Here, we report a pharmacokinetic interaction between sorafenib and the CYP3A4 inducer prednisolone in a patient with hepatocellular carcinoma (HCC).
The patient was a 72-year-old woman diagnosed with HCC. She was treated with sorafenib at 400 mg daily. On day 9, sorafenib was discontinued due to drug eruption. Nine months later, she was rechallenged with sorafenib at 400 mg daily concurrently with oral prednisolone. Prednisolone was started at 20 mg daily and was tapered by 5 mg every 14 days. We assessed the pharmacokinetics of sorafenib and its major metabolite M-2.
The concentration of sorafenib was gradually increased following tapering of prednisolone. On day 56 after rechallenge, she developed G3 oral mucositis. At this time, serum trough concentrations of sorafenib and M-2 were at 5.9 and 1.1 μg/ml, respectively. Consequently, sorafenib dosage was reduced to 200 mg daily, and the oral mucositis was attenuated. The subsequent concentrations of sorafenib and M-2 obtained with a dose of 200 mg daily ranged from 1 to 3 μg/ml and from 0.1 to 0.4 μg/ml, respectively. Computed tomography scan showed a complete response of the liver tumor with no further recurrence of the rash.
We have demonstrated for the first time that prednisolone stimulates the sorafenib metabolism and that therapeutic drug monitoring could be useful during sorafenib therapy.
索拉非尼主要在肝脏中通过 CYP3A4 介导的氧化和 UGT1A9 介导的葡萄糖醛酸化代谢。然而，关于索拉非尼的药代动力学相互作用的信息很少。在这里，我们报告了一名肝细胞癌（HCC）患者中索拉非尼与 CYP3A4 诱导剂泼尼松龙之间的药代动力学相互作用。
患者为 72 岁女性，诊断为 HCC。她每天接受 400mg 索拉非尼治疗。第 9 天，因药物疹停用索拉非尼。9 个月后，她重新开始每天服用 400mg 索拉非尼，并同时口服泼尼松龙。泼尼松龙起始剂量为每天 20mg，并每 14 天减少 5mg。我们评估了索拉非尼及其主要代谢物 M-2 的药代动力学。
随着泼尼松龙的逐渐减少，索拉非尼的浓度逐渐升高。在重新开始后的第 56 天，她出现了 G3 级口腔黏膜炎。此时，索拉非尼和 M-2 的血清谷浓度分别为 5.9μg/ml 和 1.1μg/ml。因此，将索拉非尼剂量减少至每天 200mg，口腔黏膜炎得到缓解。随后，每天 200mg 剂量下获得的索拉非尼和 M-2 的浓度分别为 1μg/ml 至 3μg/ml 和 0.1μg/ml 至 0.4μg/ml。计算机断层扫描显示肝肿瘤完全缓解，皮疹无再发。
我们首次证明泼尼松龙刺激了索拉非尼的代谢，并且在索拉非尼治疗期间进行治疗药物监测可能是有用的。
