Prediction of Losartan-Active Carboxylic Acid Metabolite Exposure Following Losartan Administration Using Static and Physiologically Based Pharmacokinetic Models

Abstract

The aim of this study was to evaluate a strategy based on static and dynamic physiologically based pharmacokinetic (PBPK) modeling for the prediction of metabolite and parent drug area under the time-concentration curve ratio (AUC/AUC) and their PK profiles in humans using in vitro data when active transport processes are involved in disposition. The strategy was applied to losartan and its pharmacologically active metabolite carboxylosartan as test compounds. Hepatobiliary transport including transport-mediated uptake, canilicular and basolateral efflux, and metabolic clearance estimates were obtained from in vitro studies using human liver microsomes and sandwich-cultured hepatocytes. Human renal clearance of carboxylosartan was estimated from dog renal clearance using allometric scaling approach. All clearance mechanisms were mechanistically incorporated in a static model to predict the relative exposure of carboxylosartan versus losartan (AUC/AUC). The predicted AUC/AUC were consistent with the observed data following intravenous and oral administration of losartan. Moreover, the in vitro parameters were used as initial parameters in PBPK permeability-limited disposition models to predict the concentration-time profiles for both parent and its active metabolite after oral administration of losartan. The PBPK model was able to recover the plasma profiles of both losartan and carboxylosartan, further substantiating the validity of this approach.

Novel in vitro dynamic metabolic system for predicting the human pharmacokinetics of tolbutamide

“…Currently, many in vitro metabolic systems have been developed to explain hepatic extraction. Kinetic parameters, such as V max and K m , can be determined in vitro using hepatocytes, microsomes, cytoplasm, the S-9 fraction or liver slices extracted from the liver of humans and other laboratory animals [8][9][10][11] . The intrinsic clearance (CL int =V max /K m under linear conditions) obtained from these models can be converted to in vivo intrinsic clearance using various scaling methods, based on the amount of enzyme present in vivo [12] .…”

Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies

“…It has also emerged that monkeys are a valuable model for the verification of hepatic disposition for transported molecules [44] particularly for substrates of the organic anion transporting polypeptide transporter [35]. Examples of complex PBPK models incorporating enzyme and transporter kinetics from in-vitro studies already exist and should become more common in the future as models evolve [46].…”

Prediction of Metabolite‐to‐Parent Drug Exposure: Derivation and Application of a Mechanistic Static Model

“…In previous work, attempts were made to test methods to project metabolite-to-parent drug ratios from in vitro metabolism and transport data using both static and dynamic physiologically-based pharmacokinetic models [4][5][6][7][8] and various assumptions and simplifications were applied. In this paper, the derivations of equations for a static mechanistic model that can be used to predict metabolite-to-parent drug ratios are presented.…”

“…Renal clearance can be estimated from scaling data from preclinical species or from in vitro studies (CL r = f u *GFR + CL sec ). 7,[11][12][13] The hepatic blood clearance values are each defined using the well-stirred model for hepatic extraction 14 that includes hepatic blood flow (Q h ), fraction unbound in blood (f u ), and hepatic free intrinsic clearance (CL int ) for each:…”