First-in-Human Predictions of Hepatic Clearance for Drugs With the Well-Stirred Model: Comparative Assessment Between Models of Fraction Unbound Based Either on the Free Drug Hypothesis, Albumin-Facilitated Hepatic Uptake or Dynamic Binding Kinetics

Abstract

The well-stirred model (WSM) is commonly used to predict the hepatic clearance in vivo (CLH) of drugs. The necessary intrinsic clearance of the unbound drug (CLint-in vitro-unbound) is generated in the in vitro assays in the presence of microsomes or hepatocytes but in the absence of plasma proteins. The value of CLint-in vitro-unbound can be extrapolated with the fraction unbound determined in vitro in plasma (fup) if the fraction unbound in vivo in liver is the same. However, this approach resulted to a systematic underprediction bias of CLH. With the goal of reducing this bias, two new models of fraction unbound were published in this journal. These models estimate the binding kinetics of the rates of association and dissociation of the drug-protein complex and propose that more dissociation in the liver compared to plasma will increase the fraction unbound available for the metabolism. Consequently, these models generated higher values of fraction unbound, implying a lower underprediction bias of CLH with the WSM. The first model was developed by Poulin et al. and is referring to the value of fup that is adjusted (fu-adjusted) to quantify the effect of a full dissociation of the drug-protein complex at the hepatocyte membrane in accordance with the theory of the albumin-facilitated hepatic uptake. A second model was developed by Yan et al. who presented a dynamic fraction unbound (fu-dynamic) measuring the real dissociation kinetics of the drug-protein complex with a new in vitro assay in the presence and absence of a recombinant liver enzyme in plasma. Therefore, the objective of this study was to make the first comparative assessment between these two models. The results indicate that, in general, the WSM combined with the values of fu-adjusted was the most accurate approach for predicting CLH. The WSM combined with the values of fu-dynamic has underperformed particularly with the acidic and neutral drugs binding to the albumin and presenting a low metabolic turnover in vitro. Therefore, the new in vitro assay for fu-dynamic resulted in an underprediction bias for these drug properties. However, the values of fu-adjusted are significantly higher than those values of fu-dynamic, and, this resulted to no underprediction bias, which is reinforcing the theory of the ALB-facilitated hepatic uptake. For the other neutral and acidic drugs, the two models of fu-dynamic and fu-adjusted are in closer agreement. Finally, for the basic drugs, the models of fu-adjusted and fu-dynamic as well as a third model only considering a pH gradient effect are almost accurately equivalent.