A Novel Unified Approach to Predict Human Hepatic Clearance for Both Enzyme- and Transporter-Mediated Mechanisms Using Suspended Human Hepatocytes

Abstract

The accurate prediction of human pharmacokinetics is critically important in modern drug discovery since it drives both pharmacological and toxicological effects. Although significant progress has been made in predicting drug disposition by hepatic drugmetabolizing enzymes, predicting transporter-mediated clearance is still highly uncertain. Furthermore, different approaches are often used to predict clearance with and without transporter involvement, hence the major clearance pathway for a compound must first be determined to know which approach to use. As a result of these challenges, a novel unified method has been developed using cryopreserved suspended human hepatocytes to predict human hepatic clearance for both enzyme-and transporter-mediated mechanisms. This method hypothesizes that, once in vitro metabolic stability is scaled by partition coefficients between hepatocytes and buffer with 4% bovine serum albumin, in vivo clearance can be better predicted. With this method, good in vitro-in vivo correlation of human hepatic clearance has been obtained for a set of 32 structurally diverse compounds, including such transporters as organic anion-transporting polypeptide substrates. The clearance predictions for most compounds are within 3-fold of observed values. This is the first time that multiple compounds result in good in vitro-in vivo extrapolation using an entirely "bottom-up" approach without any empirical scaling factor when transportermediated clearance is involved. Potential exceptions are compounds with significant biliary and/or extra-hepatic clearance. The method offers an alternative approach to more accurately predict human hepatic clearance when multiple complex mechanisms are involved.

Proteomics‐Informed Prediction of Rosuvastatin Plasma Profiles in Patients With a Wide Range of Body Weight

“…Hepatocyte uptake is used in prediction models of hepatic disposition as it is easily scaled to in vivo uptake clearance by accounting for the number of hepatocytes per gram liver (hepatocellularity). 12 Hepatocytes can also be used to simulate the influence of hepatic disposition and metabolism on pharmacokinetic (PK) profiles. [13][14][15] A disadvantage of using hepatocytes is that the influence of individual transporters cannot easily be deconvoluted.…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…Alternately, high‐affinity binding to cell‐membrane proteins, which changes the equilibrium of the nonspecific binding between drugs and plasma proteins, may lead to greater cellular uptake and clearance than currently predicted (Bowman et al, ). HHEP supplemented with 4% BSA has also been shown to be able to predict enzyme‐ and transporter‐mediated clearance without any scaling factors (Riccardi et al, ). The emerging data suggest that HHEP suspended in albumin might be a more physiologically relevant system to predict clearance and DDI.…”

Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule–Related Therapeutic Modalities

“…family, such as OATPs, OAT2, sodium-taurocholate cotransporting polypeptide, and SLC13A (Riccardi et al, 2016(Riccardi et al, , 2017(Riccardi et al, , 2019. Prospective predictions of K p,uu have been successful based on human PD data or based on clearance data using the K p,uu method (Riccardi et al, 2016(Riccardi et al, , 2017(Riccardi et al, , 2019.…”

“…family, such as OATPs, OAT2, sodium-taurocholate cotransporting polypeptide, and SLC13A (Riccardi et al, 2016(Riccardi et al, , 2017(Riccardi et al, , 2019. Prospective predictions of K p,uu have been successful based on human PD data or based on clearance data using the K p,uu method (Riccardi et al, 2016(Riccardi et al, , 2017(Riccardi et al, , 2019. Several hypotheses about the mechanisms of the effect of albumin have been developed, and increasing numbers of examples of more accurate predictions in the presence of albumin have been reported (Bowman and Benet, 2018;Mao et al, 2018;Miyauchi et al, 2018;Bowman et al, 2019).…”