Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers

Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated...

Full description

Saved in:
Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2021-06, Vol.87 (6), p.767-777
Main Authors: Kobayashi, Kazuo, Sugiyama, Erika, Shinozaki, Eiji, Wakatsuki, Takeru, Tajima, Masataka, Kidokoro, Hiyori, Aoyama, Takeshi, Nakano, Yasuhiro, Kawakami, Kazuyoshi, Hashimoto, Koki, Suenaga, Mitsukuni, Ichimura, Takashi, Ogura, Mariko, Chin, Keisho, Nakayama, Izuma, Ooki, Akira, Takahari, Daisuke, Suzuki, Wataru, Yokokawa, Takashi, Minowa, Yuichi, Hiraoka, Tomoko, Suzuki, Kenichi, Sato, Hitoshi, Hama, Toshihiro, Yamaguchi, Kensei
Format: Article
Language:English
Subjects:
Bilirubin
Cancer
Cancer Research
Colorectal cancer
Colorectal carcinoma
Enzyme inhibitors
Evaluation
Exanthema
Gene polymorphism
Hypertension
Kinases
Medicine
Medicine & Public Health
Metabolites
Metastases
Metastasis
Multivariate analysis
Oncology
Original Article
Pharmacodynamics
Pharmacokinetics
Pharmacology
Pharmacology/Toxicology
Protein-tyrosine kinase
Targeted cancer therapy
Tyrosine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) 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 C trough 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 C trough 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 C trough levels were significantly associated with the severity of hypertension or rash ( p  
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-021-04237-x