Albumin-Mediated Uptake Improves Human Clearance Prediction for Hepatic Uptake Transporter Substrates Aiding a Mechanistic In Vitro-In Vivo Extrapolation (IVIVE) Strategy in Discovery Research

Improving the Translation of Organic Anion Transporting Polypeptide Substrates using HEK293 Cell Data in the Presence and Absence of Human Plasma via PBPK Modeling

“…The results presented here align with previous work examining the hypothesis of proteinfacilitated uptake (Baik and Huang, 2015;Fukuchi et al, 2017;Bowman et al, 2019;Bteich et al, 2019;Kim et al, 2019;Bi et al, 2020;Francis et al, 2020;Liang et al, 2020;Li et al, 2021). According to this idea, interactions between the drug-protein complex and the hepatocyte cell surface or transporters may lead to greater uptake and clearance for highly protein bound drugs (primarily acidic drugs examined to date) than would be predicted using traditional in vitro methods with protein-free buffer.…”

A New Guidance for the Prediction of Hepatic Clearance in the Early Drug Discovery and Development from the in Vitro-to-in Vivo Extrapolation Method and an Approach for Exploring Whether an Albumin-Mediated Hepatic Uptake Phenomenon Could be Present Under in Vivo Conditions

“…15 Several scientists have already demonstrated with several drugs and diverse experimental settings that the unbound CL int in the liver seems to increase more than anticipated in the presence versus the absence of ALB. 2,5,[7][8][9][10][11][12][13][14][16][17][18] Consequently, specific IVIVE methods have also been developed to add some serum directly in the incubation medium, or particularly to replace the in vitro value of fu p in the IVIVEs with new scaling factors as follow 1) the experimentally-determined liver-to-plasma ratio of the unbound drug moiety, 17,18 2) the parameters of binding of the ALB-bound drug complex with the hepatocyte membrane according to the old-facilitated dissociation model, 14 3) empirically-derived factors covering the differences observed between the in vitro and in vivo unbound CL int values following regression analyses from several drug datasets, 16 and 4) an fu p value adjusted (fu p-adjusted ) to cover the in vitroto-in vivo differences in the pH gradient effect for an ionized drug and in the ALB-mediated hepatic uptake phenomenon for the drugs binding to ALB by considering the difference in the physiological concentration of ALB between the liver and plasma (or the incubation medium) . 2,5,[7][8][9][10][11][12][13] Basis of the concept of minimal and maximal cl boundaries…”

“…The consideration of drug partitioning into the liver is also another promising IVIVE method in that domain. 17,18 Hence, the old-facilitated dissociation model and liver partitioning method were also included in our new guidance that is proposed to improve the prediction of CL of drugs (Figure 1). In a perspective to further improve the CL prediction particularly in human in later stages of drug development, we have proposed to perform a validation exercise in the preclinical species prior going into human to identify which of the CL boundaries (minimal, maximal, or average) would also provide the most accurate prediction to human.…”

Is the Protein-Mediated Uptake of Drugs by Organic Anion Transporting Polypeptides a Real Phenomenon or an Artifact?

“…If the PMUE for OATP1B1 drug substrates is an artifact, it is not necessary to include albumin or plasma in OATP1B1-mediated uptake experiments because such inclusion unnecessarily complicates uptake studies and considerably raises their cost. In addition, including the PMUE in IVIVE does not appear to result in successful predictions of transporter-based CL h (Kim et al, 2019;Li et al, 2020Li et al, , 2021Bi et al, 2021).…”