Kazuo Kobayashi1,2, Erika Sugiyama3, Eiji Shinozaki4, Takeru Wakatsuki4, Masataka Tajima3, Hiyori Kidokoro3, Takeshi Aoyama5, Yasuhiro Nakano5, Kazuyoshi Kawakami5, Koki Hashimoto5, Mitsukuni Suenaga4,6, Takashi Ichimura4, Mariko Ogura4, Keisho Chin4, Izuma Nakayama4, Akira Ooki4, Daisuke Takahari4, Wataru Suzuki5, Takashi Yokokawa5, Yuichi Minowa5, Tomoko Hiraoka5, Kenichi Suzuki7, Hitoshi Sato3, Toshihiro Hama5, Kensei Yamaguchi4. 1. Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. kazuo.sugita@jfcr.or.jp. 2. Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. kazuo.sugita@jfcr.or.jp. 3. Division of Pharmacokinetics and Pharmacodynamics, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. 4. Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. 5. Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. 6. Department of Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. 7. Division of Applied Pharmaceutical Education and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Abstract
PURPOSE: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. METHODS: The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. RESULTS: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). CONCLUSION: This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.
PURPOSE: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. METHODS: The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. RESULTS: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). CONCLUSION: This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.
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