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 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 < 0.05). In a multivariate analysis, the M5 C _trough 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 C _trough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C _trough of M5 was significantly correlated with hypertension and severe rash.