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Cluster Gauss-Newton method analyses of PBPK model parameter combinations of coproporphyrin-I based on OATP1B-mediated rifampicin interaction studies


Coproporphyrin I (CP-I) is an endogenous biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B). We previously constructed a physiologically-based pharmacokinetic (PBPK) model for CP-I using clinical DDI data with an OATP1B inhibitor, rifampicin (RIF). In this study, PBPK model parameters for CP-I were estimated using the cluster Gauss-Newton method (CGNM), an algorithm used to find multiple approximate solutions for nonlinear least-squares problems. Eight unknown parameters including the hepatic overall intrinsic clearance (CLint,all ), the rate of biosynthesis (vsyn ), and the OATP1B inhibition constant of RIF(Ki,u,OATP ) were estimated by fitting to the observed CP-I blood concentrations in two different clinical studies involving changing the RIF dose. Multiple parameter combinations were obtained by CGNM that could well capture the clinical data. Among those, CLint,all , Ki,u,OATP , and vsyn were sensitive parameters. The obtained Ki,u,OATP for CP-I was 5.0- and 2.8-fold lower than that obtained for statins, confirming our previous findings describing substrate-dependent Ki,u,OATP values. In conclusion, CGNM analyses of PBPK model parameter combinations enables estimation of the three essential parameters for CP-I to capture the DDI profiles, even if the other parameters remain unidentified. The CGNM also clarified the importance of appropriate combinations of other unidentified parameters to enable capture of the CP-I concentration time course under the influence of RIF. The described CGNM approach may also support the construction of robust PBPK models for additional transporter biomarkers beyond CP-I.



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