Assessing Changes in Pharmacokinetics of Drugs in Liver Disease

Drug development for many treatment indications includes disease populations with various comorbidities. About 4.5 million American adults have liver disease and therefore, treatment populations for other diseases can have co-morbid liver disease. 

Patients with hepatic disease can have impaired capacity to eliminate drugs via the liver, and a need for dosage adjustment might arise. Dosage adjustments are typically based on bridging PK between a hepatically impaired population to a population with normal hepatic function. This requires good markers for identification and classification of the underlying hepatic impairment. Relevant biomarkers would need to be able to follow the trajectory of changes in biotransformation capacity due to changes in expression and/or function of drug metabolizing enzymes and transporters that may occur in liver disease. 

Current FDA guidance on hepatic impairment has been the standard for evaluating the impact of impaired hepatic function on the pharmacokinetics of new drugs. Challenges raised about the current approach include: 1) that these studies are often done late in the development program, 2) it can be difficult to enroll patients into a dedicated hepatic impairment study, particularly those with severe hepatic impairment, and 3) that the current markers of hepatic function, such as the Child-Pugh-Turcotte score, the Model for End-Stage Liver Disease (MELD) score and to some degree the (National Cancer Institute (NCI) score are mostly geared towards patients with cirrhosis. 

Therefore, it is timely to evaluate whether there are advances that could affect the way the impact of impaired hepatic function on the pharmacokinetic exposure and the pharmacodynamics of a drug are assessed. 

Key Topics of Discussion

• Relevant biomarkers and their predictive ability to identify changes in biotransformation and transport capacity of the liver
• Classification of degree of impairment in biotransformation and transport capacity of the diseased liver to aid drug development and dosing recommendations 
• Research on potential differences in PK in different underlying liver diseases
• Research on the potential to utilize modelling and simulation approaches to obtain dosing recommendations in patients with impaired hepatic function. 

This workshop is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award U01FD005946 totaling $5,000 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.