Glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides, but not hexadecanedioate and tetradecanedioate, detected weak inhibition of OATP1B caused by GDC-0810 in humans.

Endogenous biomarkers of drug transporters are promising tools to evaluate in vivo transporter function and potential alterations in the pharmacokinetics of their substrates. We have previously reported that coproporphyrin I/III captured the weak inhibition of OATP1B transporters by GDC-0810. In this study, we measured plasma concentrations of additional biomarkers, namely fatty acids, bile acids and their sulphate or glucuronide conjugates in the presence and absence of GDC-0810. Concentrations of hexadecanedioate and tetradecanedioate did not increase in the presence of GDC-0810. Among bile acids and their conjugates, glycochenodeoxycholate and glycodeoxycholate 3-O-glucuronides (GCDCA-3G and GDCA-3G) showed C max increases with geometric mean ratio (95% confidence interval) of 1.58 (1.13-2.22) and 1.49 (1.21-1.83), consistent with previous reports from low-dose rifampin co-administration and pharmacogenetic studies. These results suggest that GCDCA-3G and GDCA-3G are two more promising biomarkers that may capture weak OATP1B inhibition in addition to coproporphyrin I/III.