Drug-drug interaction potentials of tucatinib inhibition of human UDP-glucuronosyltransferases

Abstract

Tucatinib is known as a tyrosine kinase inhibitor (TKI), which has been commonly approved for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. However, there haven't been systematic study about the inhibition of tucatinib on UDP-Glucuronosyltransferases (UGTs) and the potential risk of drug-drug interactions (DDIs). In present study, we aimed to systematically investigate the inhibition of tucatinib on recombinant human UGTs and pooled human liver microsomes (HLMs), and to quantitatively evaluate its potential risk of DDIs by in vitro-in vivo extrapolation (IVIVE). Our data indicated that tucatinib exhibited extensive inhibition on recombinant UGTs. Tucatinib was a weak inhibitor of UGT1A4, 2B4 and 2B7; tucatinib possessed a strong inhibitory effect on UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17, with IC50 values of 0.53 μM–15.50 μM. Especially, it also potently inhibited estradiol and SN-38 glucuronidation in HLMs with IC50 values of 46.83 μM and 1.33 μM. The quantitative prediction of DDIs risk indicated that the co-administration of tucatinib with drugs mainly metabolized by hepatic or intestinal UGTs (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17) might result in potential DDIs risk through inhibition of glucuronidation. More attention should be paid to the influence of tucatinib on UGTs in liver and intestine to avoid unnecessary clinical DDIs risk.