%0 Journal Article %A Venkatesh Pilla Reddy %A Barry C Jones %A Nicola Colclough %A Abhishek Srivastava %A Joanne Wilson %A Danxi Li %T An investigation into the prediction of the plasma concentration-time profile and its inter-individual variability for a range of flavin-containing monooxygenase substrates using a mechanistic physiologically based pharmacokinetic modelling approach %D 2018 %R 10.1124/dmd.118.080648 %J Drug Metabolism and Disposition %P dmd.118.080648 %X Our recent paper (Jones et al., 2017) demonstrated the ability to predict in vivo clearance of Flavin-containing Monooxygenases (FMO) drug substrates, using in vitro human hepatocyte and human liver microsomal intrinsic clearance (CLint) with standard scaling approaches. In this paper, we apply physiologically based pharmacokinetic (PBPK) modelling & simulation approaches (M&S) to predict the clearance, AUC and Cmax together with the plasma profile of a range of drugs from the original study. The human physiological parameters for FMO, such as enzyme abundance in liver, kidney, gut were derived from in vitro data and clinical pharmacogenetics studies. The drugs investigated include itopride, benzydamine, tozasertib, tamoxifen, moclobemide, imipramine, clozapine, ranitidine, and olanzapine. The fraction metabolised (Fm) by FMO for these drugs ranged from 21 to 96%. The developed PBPK models were verified with data from multiple clinical studies. An attempt was made to estimate the scaling factor for recombinant FMO (rFMO) using a parameter estimation approach and an automated sensitivity analysis (ASA) within the PBPK platform. Simulated oral clearance (CLpo), using in vitro hepatocyte data and associated extrahepatic FMO data, predicts the observed in vivo plasma concentration profile reasonably well and predicts AUC for all of the FMO substrates within 2-fold of the observed clinical data, while, 7 out of 9 compounds fell within 2-fold when human liver microsomal data was used. rFMO over-predicted the AUC by approximately 2.5-fold for 3 out of 9 compounds. Applying a calculated inter-system extrapolation scalar or tissue specific scalar for rFMO data resulted in better prediction of clinical data. PBPK M&S results from this study demonstrate that human hepatocytes and human liver microsomes can be used along with our standard scaling approaches to predict human in vivo PK parameters for FMO substrates. %U https://dmd.aspetjournals.org/content/dmd/early/2018/06/12/dmd.118.080648.full.pdf