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Substrate-dependent Inhibition & Time-dependent Inhibition of OATP1B & its Impact on DDI Prediction
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Substrate-dependent Inhibition & Time-dependent Inhibition of OATP1B & its Impact on DDI Prediction

Presented by: Yuichi Sugiyama, Ph.D., RIKEN

Monday, November 18, 2019

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Abstract:

1) Substrate-dependent and/or pre-incubation time dependent Ki values of OATP1Bs inhibitors; OATP1B is involved in the hepatic uptake of various anionic drugs, and drug-drug interactions (DDIs) can be caused by OATP1B inhibition. To address this issue, in vitro cell-based inhibition assay is routinely performed at nonclinical stages, and accurate determination of Ki values is critical to quantitatively assess the risk of DDIs. However, large interlaboratory variability was reported in the Ki values. The underlying mechanisms are not fully understood, but substrate- and time-dependent inhibition of OATP1B1 are considered to account at least in part for the variability. 
Recent reports provided quantitative predictions for OATP1Bs-mediated DDIs between statins and cyclosporine A(CsA)/rifampicin (RIF) based on PBPK models. In the process of the analyses, the in vitro–in vivo discrepancies in the Ki values for OATPs were suggested. Such discrepancies may hamper the practical use of PBPK modeling for DDI prediction via a bottom-up approach, in which model parameters are determined by scaling up in vitro experimental results. To make a bottom-up predictions of OATP1Bs mediated DDI successful, substrate dependent and pre-incubation time dependent Ki values should be kept in mind.  Such a pre-incubation time dependent Ki values may be due to the trans-inhibition mechanism. 

In the process of the analyses, the in vitro–in vivo discrepancies in the Ki values for OATPs  and substrate dependent change of Ki values of  inhibitors were clarified. Such discrepancies and substrate dependency may hamper the practical use of PBPK modeling for DDI prediction by using endogenous biomarker. We therefore considered such substrate dependent change in Ki values between endogenous substrates and probe substrates obtained from in vitro experiment in the prediction of DDI as shown below.
 

2) Can Endogenous Biomarkers be Applied in Phase I Clinical Trials to Facilitate Subject Phenotyping and DDI Prediction? Earlier assessment of DDI risk in humans saves cost and time in conducting clinical DDI studies with minimal or negligible impact of DDI. Recent progress in the endogenous compounds that may be used as biomarkers for assessing DDI and genetic polymorphism based interindividual differences involving hepatic transporters in humans will be shown. Clinical investigations demonstrated that the AUC of endogenous substrates, such as coproporphyrins(CP), total and direct bilirubin, and some sulfate and glucuronide conjugates of bile acids, shows a significant correlation with an OATP1B substrate drugs such as statins, in terms of its inhibition by rifampicin(RIF), supporting the idea that endogenous substrates have adequate performance as probes for the quantitative analysis of transporter-mediated DDIs. We have started the construction of PBPK modeling of the endogenous substrates bilirubin, bilirubin glucuronide, CP-I, and glycochenodeoxycholate-3-sulfate. Such a PBPK model can reasonably account for these drugs’ interactions with rifampicin. PBPK modeling and simulation may help in the extrapolation of OATP1B-mediated change in plasma concentration of endogenous substrates to those of probe drug substrates.


About the Speaker:

  Dr. Yuichi Sugiyama started working as the Head of Sugiyama Laboratory in RIKEN, Yokohama, Japan since 2012. He had been Professor, Department of Molecular Pharmacokinetics at the University of Tokyo since 1991; when he retired from the University of Tokyo in March, 2012 and joined RIKEN. He has made and continues to make internationally acclaimed contributions to the pharmaceutical sciences in diverse areas. These include physiologically-based pharmacokinetic modelling, the prediction of drug clearance from in vitro data, the quantitative prediction of transporter and enzyme mediated drug-drug interactions based on in vitro studies. His work is internationally recognized by many awards, including the American Association of Pharmaceutical Scientists Distinguished Pharmaceutical Scientist Award in 2003, the International Pharmaceutical Federation (FIP) Hoest Madsen Medal in 2009, the Medal with Purple Ribbon, a Medal of Honor given by the Japanese Government in 2010, the BB Brodie Award from the American Society for Pharmacology and Experimental Therapeutics in 2012, the RT Williams Distinguished Scientific Achievement Award from the International Society for the Study of Xenobiotics (ISSX) in 2013 and Rawls-Palmer Progress in Medicine Award from American Society for Clinical Pharmacology and Therapeutics in 2014.  Dr. Sugiyama was listed as a top (#1) scientist in 2007 for the number of citations he received in the preceding 10 years in the field of pharmacology and toxicology. He served as the chairman of Board of Pharmaceutical Sciences in FIP (2000-2004). He was also the president of both ISSX and the Japanese Society for Xenobiotic Metabolism and Disposition (2006-2007).