Mechanistic Pharmacokinetic Modeling for the Prediction of Transporter-Mediated Disposition in Humans from Sandwich Culture Human Hepatocyte Data

Abstract

ABSTRACT:With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that for compounds with passively mediated pharmacokinetics (PK). In this study, we have assessed the predictability of human PK for seven organic aniontransporting polypeptide (OATP) substrates (pravastatin, cerivastatin, bosentan, fluvastatin, rosuvastatin, valsartan, and repaglinide) for which clinical intravenous data were available. In vitro data generated from the sandwich culture human hepatocyte system were simultaneously fit to estimate parameters describing both uptake and biliary efflux. Use of scaled active uptake, passive distribution, and biliary efflux parameters as inputs into a PBPK model resulted in the overprediction of exposure for all seven drugs investigated, with the exception of pravastatin. Therefore, fitting of in vivo data for each individual drug in the dataset was performed to establish empirical scaling factors to accurately capture their plasma concentration-time profiles. Overall, active uptake and biliary efflux were under-and overpredicted, leading to average empirical scaling factors of 58 and 0.061, respectively; passive diffusion required no scaling factor. This study illustrates the mechanistic and model-driven application of in vitro uptake and efflux data for human PK prediction for OATP substrates. A particular advantage is the ability to capture the multiphasic plasma concentration-time profiles for such compounds using only preclinical data. A prediction strategy for novel OATP substrates is discussed.

Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling

“…The scaling factor obtained in rats between in vitro hepatic uptake and in vivo observation was applied to the model in order to predict the observed human PK. In the sandwich culture hepatocytes, the Cl int,T was determined to be 1.9 µL/min/million cell at 1 µM of pravastatin 8. When these in vitro data were directly used in the PBPK model, it failed to capture the curve of the time concentration profile of pravastatin administered intravenously 8, 9.…”

“…No additional scaling factor was applied for the prediction of uptake by the OATP transporter. The input for passive diffusion is 0.0001 mL/min/10 6 cells determined in sandwich culture hepatocytes 8. The canalicular efflux by MRP2 was described using a measured Cl int,T (1.2 µL/min/10 6 cells) in sandwich culture hepatocytes8 with a scaling factor of 0.18 9…”

“…A Cl int,T (1.2 µL/min/cm 2 ) was used for the intestinal MRP2 with the scaling factor of 0.18 8. The MechPeff model was used to predict the permeability 26.…”

“…In the Simcyp default compound profile, in order to describe the clinical data, the OATP Cl int,T input of hepatic uptake parameter for pravastatin was back calculated by fitting to the observed in vivo PK data. In the other studies,5, 7, 8, 9 the in vitro OATP Cl int,T data generated in the suspended hepatocytes and the sandwich cultured hepatocytes were used. Nevertheless, when the in vitro data were incorporated into the PBPK model, a scaling factor was found to be necessary in order to predict the observed pravastatin PK profile accurately.…”

“…Nevertheless, when the in vitro data were incorporated into the PBPK model, a scaling factor was found to be necessary in order to predict the observed pravastatin PK profile accurately. It is evident that a different scaling factor is needed for different OATP substrates despite the in vitro data being generated in the same laboratory 8. This phenomenon demonstrates an important hurdle to the utilization of the in vitro data for prospective PK prediction of a new chemical entity (NCE) that is a substrate of OATP by PBPK modeling.…”