High Risk of Drug–Drug Interactions Caused by Pexidartinib via UDP-Glucuronosyltransferases Inhibition

Since pexidartinib was approved by the FDA for adult patients with tenosynovial giant cell tumor, increasing attention has been paid to its high frequency of adverse reactions. This study purposes to investigate the risk potential of pexidartinib-associated drug–drug interactions (DDIs) from the perspective of UDP-glucuronosyltransferases (UGTs) inhibition. Our results demonstrated that pexidartinib was a pan-inhibitor of UGTs, and it exhibited broad inhibition against 11 human recombinant UGT isoforms at clinically achievable concentrations, with IC 50 values ranging from 0.97 to 20.02 μM. Further inhibition kinetic analysis showed that pexidartinib competitively inhibited UGT1A1, UGT1A6, UGT1A7, and UGT1A9, while exhibiting mixed inhibition toward UGT2B15. The K i,u values for them were calculated to be 4.27 ± 0.28, 1.72 ± 0.12, 1.67 ± 0.11, 0.65 ± 0.13, and 2.37 ± 0.45 μM, respectively. The results of in vitro – in vivo extrapolation (IVIVE) indicated that coadministration of pexidartinib at a clinically approved dose (400 mg twice daily) with the drugs primarily cleared by UGT1A1, UGT1A6, UGT1A7, UGT1A9, and UGT2B15 would result in a higher risk of DDI. In summary, our results provide useful information for the mechanism underlying pexidartinib-induced hepatotoxicity and clinical safe medication of pexidartinib.