Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data

Abstract

The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (K (m,u) = 28.4 +/- 3.7 muM, V (max) = 1318 +/- 176 pmol/mg/min and P (dif) = 1.21 +/- 0.42 microl/mg/min) compared to human hepatocytes (K (m,u) = 44.4 +/- 14.6 microM, V (max) = 304 +/- 85 pmol/mg/min and P (dif) = 0.724 +/- 0.271 microl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration-time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CL(P)) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

“…Whereas predicting PK of transporter substrates remains a challenge, several groups have proposed PBPK models to improve prediction by incorporating active uptake and/or biliary clearance estimated from in vitro data (Poirier et al, 2009;Watanabe et al, 2009;Jones et al, Fig. 5.…”

“…Assessing Kp values is challenging because methods to acquire data in humans are lacking. Kp values in PBPK models available in preclinical development are usually estimated using in silico methods and tissue composition (Poirier et al, 2009;Watanabe et al, 2009;Jones et al, 2012). Early in silico methods focused on water-lipid partitioning in tissues (Poulin and Theil, 2000).…”

“…However, these models would not be expected to provide reasonable predictions for compounds that are actively transported. To improve predictions for transporter substrates, in vitro assays assessing active processes have been developed, and the active uptake rates estimated from these assays have been integrated into PBPK models (Poirier et al, 2009;Watanabe et al, 2009;Jamei et al, 2014). In these models, reasonable predictions for substrates of liver transporters are achieved only when empirical in vitro-to-in vivo extrapolation scaling factors (SFs) are applied.…”

Use of Mechanistic Modeling to Assess Interindividual Variability and Interspecies Differences in Active Uptake in Human and Rat Hepatocytes

“…Application of the mechanistic model developed to describe the interplay among multiple processes was previously assessed in rat hepatocytes and extended here to human hepatocytes; hence, the interspecies differences in uptake kinetics of seven OATP substrates were investigated. This investigation is of particular relevance because the data generated in rat hepatocytes are valuable to improve our understanding of mechanisms driving the disposition of the compound using physiologically based pharmacokinetic models and subsequent translation to human transporter-mediated pharmacokinetics (Poirier et al, 2009;Watanabe et al, 2009). Although the similarities and differences in metabolizing enzymes between rat and human are acknowledged (Martignoni et al, 2006;Hagenbuch and Gui, 2008;Kotani et al, 2011), a limited number of studies have elucidated the details of species differences in substrate specificities and activity of uptake transporters (Hagenbuch and Meier, 2004;Nakakariya et al, 2008).…”

Permeability Comparison between Hepatocyte and Low Efflux MDCKII Cell Monolayer

“…Furthermore, such information is critical for liver targeting projects where compounds with low passive permeability and high active uptake by liver specific transporters (for example, organic anion transporter polypeptide (OATP) 1B1 and 1B3) are identified in order to achieve high free drug concentration in the liver, while maintaining minimal systemic and peripheral tissue exposure to reduce toxicity (5)(6)(7). When predicting clinical outcomes using physiologically based pharmacokinetic models for transporter substrates and inhibitors, passive permeability across hepatocytes is an important input parameter to accurately model human pharmacokinetics, free liver drug concentration, and drug-drug interaction potentials (8).…”