Pharmacokinetic interaction between regorafenib and atorvastatin in rats

Abstract

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_REG+ATO), a carrier with regorafenib (II_REG), and atorvastatin with a carrier (III_ATO). 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_REG+ATO group, the C_max, AUC_0–t, and AUC_0–∞ of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the C_max, AUC_0–t, and AUC_0–∞ of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC_0–t and AUC_0–∞ 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.

Graphical abstract