Senior Research Investigator Bristol Myers Squibb, United States
Disclosure(s):
Xinxin Yang, PharmD: No financial relationships to disclose
Objectives: Coproporphyrin-I (CP-I) has been proposed as a biomarker for assessing organic anion transporting polypeptide (OATP) 1B functions in supporting the quantitative understanding of OATP1B- mediated drug-drug interactions (DDIs). This project aims to evaluate the performance of the CP-I physiologically based pharmacokinetic (PBPK) model in Simcyp™ V23 and demonstrate its applicability in the early assessment of OATP1B inhibition risk of investigational drugs.
Methods: Plasma concentrations of CP-I were measured from clinical DDI or single ascending dose studies to assess the OATP1B inhibition for portfolio drug candidates, as well as known OATP1B inhibitors, rifampin and gemfibrozil. PBPK models for the portfolio drug candidates were developed, and the default model files of rifampin, gemfibrozil, and CP-I were used. Simulations were performed using Simcyp™ V23. The predicted and observed relative exposure changes, specifically the maximum concentration ratio (Cmax R) and area under the curve ratio (AUCR) of CP-I following administration of drug candidates or OATP1B inhibitors, were compared and assessed against Guest criteria. Sensitivity analyses were conducted on the in vitro Ki values of the drug candidates to determine the extent of reduction required to capture the clinically observed ratios.
Results: Case 1: simulated CP-I profiles closely matched clinical data, capturing the significant increase following rifampin administration. The predicted Cmax ratio (4.2) aligned well with the observed 414% increase from baseline. Case 2: Following gemfibrozil administration, CP-I exposure was elevated. The model predicted geometric mean ratios of Cmax and AUC0-16hr of 1.68 and 1.41, and compared favorably with observed values of 1.32 and 1.32, respectively. Case 3: No dose-dependent CP-I increase was observed across the tested doses of investigational Drug A. To evidence CP-I clinical changes, at least 50-fold reduction in the in vitro Ki value was required. The totality of data from clinical observation, PBPK simulation and in vitro information suggested that Drug A did not inhibit OATP1B1 at the clinically relevant doses. Case 4: Drug B showed potential to inhibit breast cancer resistance protein (BCRP) and OATP1B1 in vitro, while rosuvastatin exposure was doubled when coadministered with Drug B in the clinical study. PBPK simulation predicted a slight increase in CP-I level, however, this contrasted with the observed AUCR of 0.77 for CP-I following Drug B administration, indicating that the increased rosuvastatin exposure was primarily due to BCRP inhibition rather than hepatic OATP1B inhibition.
Conclusions: The CP-I PBPK model in Simcyp™ V23 reasonably described observed CP-I exposure changes following administration of various portfolio drug candidates or known OATP1B inhibitors. These findings support the utility of CP-I as an endogenous biomarker for OATP1B activity and highlight the potential of PBPK modeling approaches in facilitating a mechanistic understanding of complex drug-drug interactions during drug development.
