Pexidartinib Triggers the Risk of Drug-drug Interactions by Inhibiting UDP-glucuronosyltransferase in vitro

Abstract

Pexidartinib is the first FDA approved drug for adult patients with tenosynovial giant cell tumor that are not amenable to improvement with surgery. In vitro data has showed pexidartinib is likely to inhibit UDP-glucuronosyltransferase (UGT) 1A1 at clinically relevant concentrations. However, the effects of pexidartinib against other UGT have not been fully characterized. Therefore, this study purpose to investigate the inhibitory effects of pexidartinib against UGT, as well as to quantitatively evaluate drug adverse reactions by UGTs inhibition. Our results indicated that pexidartinib exhibited potent inhibition of UGT1A1, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, and 2B15, with a range of IC values of 0.97-20.02 μM. Pexidartinib displayed competitive inhibition towards UGT1A1, UGT1A6, UGT1A7 and UGT1A9, while mixed inhibited UGT2B15. The K values for them were calculated to be 4.27 ± 0.28 μM, 1.72 ± 0.12 μM, 1.67 ± 0.11 μM, 0.65 ± 0.13 μM, and 2.37 ± 0.45 μM, respectively. Co-administration of pexidartinib at the clinically approved dose (400 mg twice daily) with drugs primarily cleared by UGT1A1, UGT1A6, UGT1A7, UGT1A9, and UGT2B15 would likely result into increase of drug-drug interactions risk.