Pharmacokinetic interaction between regorafenib and atorvastatin in rats.

Background: Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug-drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites.

Methods: Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (I), a carrier with regorafenib (II), and atorvastatin with a carrier (III). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model.

Results: A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the I group, the C, AUC, and AUC of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the C, AUC, and AUC of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC and AUC of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively.

Conclusions: This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.