New IVIVE method for the prediction of total human clearance and relative elimination pathway contributions from in vitro hepatocyte and microsome data

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• 作者：Julia Riede^a ; ^b ; Birk Poller^a ; Ken-ichi Umehara^a ; Jö ; rg Huwyler^b ; Gian Camenisch^a ; ^{gian.camenisch@novartis.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AFE ; average fold error ; CLh ; hepatic clearance ; CLint ; intrinsic clearance ; CLint ; h ; intrinsic hepatic clearance ; CLint ; met ; intrinsic metabolic clearance ; CLint ; sec ; intrinsic secretory clearance ; CLren ; renal clearance ; CLtot ; total clearance ; CYP ; cytochrome P450 ; ECCCS ; Extended Clearance Concept Classification System ; ECM ; Extended Clearance Model ; fnh ; fraction of hepatic elimination ; fnmet ; fraction of metabolic elimination ; fnren ; fraction of renal elimination ; fnsec ; fraction of biliar
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：30 April 2016
• 年：2016
• 卷：86
• 期：Complete
• 页码：96-102
• 全文大小：571 K

文摘

Total human clearance is a key determinant for the pharmacokinetic behavior of drug candidates. Our group recently introduced the Extended Clearance Model (ECM) as an accurate in vitro–in vivo extrapolation (IVIVE) method for the prediction of hepatic clearance. Yet, knowledge about relative elimination pathway contributions is needed in order to predict the total human clearance of drug candidates. In the present work, a training set of 18 drug compounds was used to describe the affiliations between in vitro sinusoidal uptake clearance and the fractional contributions of hepatic (metabolic and biliary) or renal clearance to overall in vivo elimination. By means of these quantitative relationships and using a validation set of 10 diverse drug molecules covering different (sub)classes of the Extended Clearance Concept Classification System (ECCCS), the relative contributions of elimination pathways were calculated and demonstrated to well correlate with human reference data. Likewise, ECM- and pathway-based predictions of total clearances from both data sets demonstrated a strong correlation with the observed clinical values with 26 out of 28 compounds within a three-fold deviation. Hence, total human clearance and relative contributions of elimination pathways were successfully predicted by the presented method using solely hepatocyte and microsome in vitro data.