Population Pharmacokinetic Modeling of Glycochenodeoxycholic Acid 3‐O‐Sulfate ( <scp>GCDCA</scp> ‐S) as Endogenous Biomarker of <scp>OATP1B3</scp> and <scp>OAT3</scp> Transporters

Endogenous biomarkers for drug transporters are an emerging tool for the assessment of transporter-mediated drug-drug interactions (DDI). Glycochenodeoxycholic acid 3-O-sulfate (GCDCA-S) has been proposed as a Tier 2 biomarker of hepatic OATP1B3 and renal OAT3 transporters by the International Transporter Consortium. However, there are currently no mechanistic models developed for this biomarker. This study aimed to characterize the synthesis and elimination of this biomarker through population pharmacokinetic (POP-PK) modeling of GCDCA-S plasma and urine data in the presence and absence of OATP1B inhibitor rifampicin and OAT3 inhibitor probenecid. Simultaneous fitting of rifampicin and probenecid interaction data incorporated the inhibitory effect of rifampicin on GCDCA-S hepatic clearance (CL_h) and probenecid inhibitory effect on both renal (CL_R) and hepatic (CL_h) clearance parameters, assuming no effect on the synthesis of GCDCA-S. The POP-PK model successfully described the observed data for GCDCA-S, with reasonable standard errors (<40%) for population parameter estimates. The results indicated biliary excretion as the primary route of elimination for GCDCA-S (~ 95%). The GCDCA-S model was successfully verified against four independent datasets on plasma baseline and interaction after rifampicin administration. Power calculations confirmed the sensitivity of GCDCA-S for identifying weak to strong OATP1B3 and OAT3 inhibitors using plasma AUC and renal clearance as metrics, respectively. This study provides further validation of GCDCA-S as an endogenous biomarker of OATP1B3 and OAT3 transporters and offers a valuable resource for optimizing the design of prospective OATP1B3- and OAT3-mediated DDI studies in early-phase clinical trials.