Review article: time to revisit Child‐Pugh score as the basis for predicting drug clearance in hepatic impairment

Abstract

Summary: Background: Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child‐Pugh score. Child‐Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity. Aims: To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients. Methods: Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically‐based pharmacokinetic (PBPK) modelling. Results: PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug‐metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically‐impaired populations. These variables might not correlate with Child‐Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child‐Pugh score. Conclusions: Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child‐Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child‐Pugh alternatives are recommended to allow better prediction of drug exposure.