Background

Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography.

Methods

We measured the trough blood concentrations (C_trough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the C_trough and therapeutic outcomes of regorafenib was analyzed.

Results

In patients who were receiving regorafenib 40–160 mg/day, the C_trough values of regorafenib, M2, and M5 were 318–9467, 34–3594, and 38–3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the C_trough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the C_trough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification.

Conclusions

The use of regorafenib may not be suitable in patients with a low C_trough value. To prevent skin toxicities, the C_trough value of M5 should be monitored.

中文翻译：

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瑞格非尼及其代谢产物M5的治疗药物监测可以预测治疗效果和皮肤毒性的发生。

背景

Regorafenib是一种多重酪氨酸激酶抑制剂，已被批准用于治疗对化疗有抗药性的癌症，其中包括晚期结直肠癌，胃肠道间质瘤和肝细胞癌。但是，这种药物会引起不良事件，包括皮肤毒性，在大约75％的情况下需要调整剂量。目前，尚未在临床环境中评估雷戈非尼的血药浓度。因此，我们最近开发了一种可以使用高效液相色谱法评估药物血药浓度的方法。

方法

我们使用高效液相色谱法分别测量了14和4例晚期结直肠癌和胃肠道间质瘤患者中雷戈非尼及其代谢产物（M2和M5）的谷血浓度（C_谷）。然后，分析了C_波谷与瑞格非尼治疗效果之间的相关性。

结果

在接受瑞格非尼40–160 mg /天的患者中，瑞格非尼，M2和M5的C_谷值分别为318–9467、34–3594和38–3796 ng / mL。值的差异是显着的。尽管尚未阐明影响这种差异的具体因素，但即使以标准剂量给药，雷戈非尼的C_谷值仍在某些患者中极低，这可能解释了较低的反应率。此外，M5的C_谷值与皮肤毒性的发生率显着相关，这是剂量改变的最常见原因。

结论

C_波谷值低的患者可能不适合使用瑞戈非尼。为防止皮肤中毒，应监测M5的C_谷值。