TY - JOUR T1 - GDC-0810 pharmacokinetics and transporter-mediated drug interaction evaluation with an endogenous biomarker in the first-in-human, dose escalation study JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.087924 SP - dmd.119.087924 AU - Kit Wun Kathy Cheung AU - Kenta Yoshida AU - Sravanthi Cheeti AU - Buyun Chen AU - Roland Morley AU - Iris T Chan AU - Srikumar Sahasranaman AU - Lichuan Liu Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/07/02/dmd.119.087924.abstract N2 - GDC-0810 is an orally bioavailable, selective estrogen receptor (ER) degrader developed to treat ER-positive breast cancer. A first-in-human (FIH) dose escalation phase I study (n=41) was conducted to characterize the pharmacokinetics (PK) of GDC-0810 and its two major metabolites. GDC-0810 demonstrated linear PK from 100 mg QD to 600 mg QD. The mean terminal half-life following a 600 mg single dose was approximately 8 hours. Since GDC-0810 is a potent in vitro inhibitor of organic anion transporting polypeptide (OATP) 1B1/3, the kinetic profile of coproporphyrin I (CPI), a promising endogenous biomarker for OATP1B1/3, was analyzed retrospectively in a subset of the plasma samples collected in the same FIH study. CPI exhibited a GDC-0810 dose-dependent increase, suggesting in vivo inhibition of OATP1B transporters. To quantitatively predict the magnitude of OATP1B-mediated drug-drug interactions (DDI) with pravastatin (a known OATP1B substrate), the in vivo unbound inhibition constant was first estimated using a one-compartment model, and then incorporated to a physiologically-based pharmacokinetic model. The model showed some under-estimation of the magnitude of DDI when compared to a clinical DDI study result, while prediction had a relatively large uncertainty due to the small effect size, limited sample size, and variability in CPI kinetics. In conclusion, this study characterized the pharmacokinetic profiles of GDC-0810 in breast cancer patients and demonstrated the utility of CPI to detect OATP1B-mediated DDI of a new molecular entity as early as FIH study.SIGNIFICANCE STATEMENT Endogenous biomarkers of transporters have recently been shown to be promising tools to evaluate the risk of clinical transporter-mediated DDIs. This is the first study to report pharmacokinetic interaction between an investigational molecule and a transporter biomarker in the first-in-human study. The observed interaction and model-based analysis, and prediction provide important insights on the novel approach to quantitatively predict transporter-mediated DDI as early as FIH studies in the clinical development. ER -