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Title: Application of sandwich-cultured hepatocytes and the B-Clear assay for the IVIVE of hepatic clearance, drug-drug interactions and unbound intracellular drug concentrations.
Speaker: Birk Poller, Ph.D, Lab Head, PK Sciences Department, Novartis, Basel
Date and Time: 21 June 2017, Wednesday
10:00 AM (CET) 9:00 AM (GMT) 11:00 AM (IST, Israel) 5:00 PM (Tokyo, Seoul) 4:00 PM (Beijing)
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Summary
Sandwich-cultured hepatocytes (SCH) grown between two layers of collagen and matrigel are characterized by a polarized morphology and by the formation of biliary networks. In contrast to suspended hepatocytes, SCH express the relevant hepatic uptake and efflux transporters, which are involved in the hepatobiliary disposition of drugs and endogenous compounds. The B-Clear assay allows determining the biliary secretion process in vitro using SCH. This parameter has been incorporated in different in vitro-in vivo extrapolation (IVIVE) applications for hepatobiliary clearance and disposition: 1. Traditionally hepatic clearance predictions have been performed based on metabolic stability data from liver microsomes or hepatocytes. However, IVIVE for drugs that are actively excreted into bile requires a quantitative measure of the biliary clearance process, obtained from the B-Clear assay. Applying in vitro process clearances for biliary secretion, hepatic uptake and metabolism to the extended clearance model (ECM) provided successful predictions of the hepatic organ clearance in rat and human. 2. Mechanistic insights in the hepatic drug-drug interaction potential of statins were obtained from the in vitro based ECM. Thereby, incorporation of biliary secretion data has been demonstrated to be crucial for drugs that are secreted into bile. 3. Risk assessments for the inhibition of intrahepatic DDI or toxicity targets have previously been assessed using unbound systemic drug exposure under assumption of the “free drug hypothesis”. This concept, however, is unlikely valid as unbound intrahepatic drug concentrations are affected by active sinusoidal and biliary transport and by metabolism. Therefore, the ECM has been applied to determine the in vitro liver-to-blood partition coefficients (Kp,uu) for drugs that inhibit BSEP in vitro. Correlation of unbound intrahepatic drug concentrations, obtained from clinical unbound systemic concentrations and measured Kp,uu, with BSEP IC50 data allowed to estimate the risk for observed drug-induced cholestasis in clinics.
Biography
Dr. Poller has been employed at Novartis since 2010 as a laboratory head for in vitro drug transporter studies. Dr. Poller is interested in the interplay between transport and metabolic processes in the areas of clearance IVIVE, drug-drug interaction assessments and drug classification systems such as the EC3S. He contributed to the establishment of novel methods for hepatic and renal IVIVE as well as for intracellular concentration-based risk assessments of drug-induced cholestasis. In addition Dr. Poller acts as DMPK expert in cross-functional project teams during (pre-)clinical development and is familiar with PBPK modeling software for clinical DDI simulations. Dr. Poller obtained his Ph.D from the University of Basel, Switzerland focusing on cellular blood-brain barrier models. He then continued his research on efflux transporter interplay at the blood-brain barrier as a postdoctoral fellow in the group of Dr. Alfred Schinkel at the Netherland Cancer Institute in Amsterdam. Dr. Poller’s academic and industrial research projects resulted in 20 peer-reviewed manuscripts and he gave presentations at several scientific meetings.
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