Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization

Abstract

Development of new chemical entities is costly, time-consuming, and has a low success rate. Accurate prediction of pharmacokinetic properties is critical to progress compounds with favorable drug-like characteristics in lead optimization. Of particular importance is the prediction of hepatic clearance, which determines drug exposure and contributes to projection of dose, half-life, and bioavailability. The most commonly employed methodology to predict hepatic clearance is termed in vitro to in vivo extrapolation (IVIVE) that involves measuring drug metabolism in vitro, scaling-up this in vitro intrinsic clearance to a prediction of in vivo intrinsic clearance by reconciling the enzymatic content between the incubation and an average human liver, and applying a model of hepatic disposition to account for limitations of protein binding and blood flow to predict in vivo clearance. This manuscript reviews common in vitro techniques used to predict hepatic clearance as well as current challenges and recent theoretical advancements in IVIVE.

Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin

“…Herb-herb interactions, inducing changes in the solubility or generation of a new compound, may occur during the decoction process. Liver and gut microbes play an important role in drug metabolism (Knudsen et al, 2021;Sodhi and Benet, 2021). Thus, chemical transformations or endogenous metabolism of amygdalin was investigated during decoction and incubation of the rat liver microsome (RLM) and gut microbial enzyme (RGME) preparations, respectively.…”

Does Addition of Protein to Hepatocyte or Microsomal In Vitro Incubations Provide a Useful Improvement in In Vitro-In Vivo Extrapolation Predictability?

“…Metabolic stability studies are routinely conducted to predict in vivo drug clearance for metabolized drugs in the early drug discovery stage, where various approaches to predict in vivo clearance from in vitro systems, such as utilization of microsomes and hepatocytes, have been established as recently reviewed (Sodhi and Benet, 2021). Attempting to predict in vivo hepatic clearance using the in vitro-in vivo extrapolation (IVIVE) method involves measuring an intrinsic clearance (CL int ), defined as the intrinsic ability of liver to remove drug in the absence of protein binding or flow limitations in microsomes or hepatocytes, and applying biological scaling factors and a liver model to scale the in vitro measures to predict the in vivo hepatic clearance.…”

Can In Vitro–In Vivo Extrapolation Be Successful? Recognizing the Incorrect Clearance Assumptions

“…The IVIVE process utilizes a model of hepatic elimination that includes measures of blood flow to the organ of elimination, fraction of drug unbound in the systemic circulation, and a measure of the intrinsic ability of the liver to eliminate drug independent of organ blood flow and protein binding. It is this intrinsic elimination measure that is scaled‐up from the in vitro hepatocyte and microsome studies as we recently reviewed 1 . However, IVIVE is not sufficiently successful, with only about one third of human drug hepatic clearance being predicted within twofold of measured human drug clearance values 2,3 .…”

“…It is this intrinsic elimination measure that is scaled-up from the in vitro hepatocyte and microsome studies as we recently reviewed. 1 However, IVIVE is not sufficiently successful, with only about one third of human drug hepatic clearance being predicted within twofold of measured human drug clearance values. 2,3 During these past 6 years, our laboratory has published 16 papers, addressing a multitude of issues, slowly peeling the onion-like problem, recognizing today that the failure of IVIVE is due primarily to theoretical issues and realizing now that our laboratory, in good part, may be responsible for the failure of the IVIVE process.…”