The liver is responsible for the metabolism and clearance of many different drugs and their metabolites. Because of the liver’s importance in removing drugs from the body, diseases or injuries that impair liver function (hepatic impairment) can affect how some drugs interact with the body. In particular, the pharmacokinetics (PK) of the drug may be altered in a way that increases (or decreases) exposure to the parent drug or one or more of its metabolites. This, in turn, can negatively impact the drug’s safety (by increased exposure to a more toxic dose range for the drug) and/or effectiveness (by reduced exposure to a pharmacologically active metabolite of the drug). Common diseases that have been shown to impact drug processing by the liver include alcoholic liver disease, cirrhosis, and chronic hepatitis infections. With the liver’s broad potential to impact drug pharmacokinetics, it is important to consider when special PK studies in subjects with impaired liver function are necessary and how to conduct them. Information from hepatic impairment studies can provide critical support to the approval package and product labeling; specifically, this will include dose recommendations or adjustments in individuals with hepatic impairment.
When an Impaired Hepatic Function Study May Be Necessary
The US Food and Drug Administration (FDA) issued Guidance in 2003 on PK studies in patients with impaired hepatic function. The purpose of these studies is to determine if impaired liver function substantially impacts drug exposure. The results of hepatic impairment studies and any recommendations for dosage adjustment are included in the product label. A PK study in participants with impaired liver function will be important if:
- Liver metabolism or excretion of a drug or an active metabolite is >20% of the absorbed drug
- The drug has a narrow therapeutic index
- The extent of metabolism is unknown, and there is no available information suggesting that elimination by the liver is minor
There are some drugs where PK is unlikely to be affected by hepatic impairment, including drugs excreted entirely by the kidneys (renal), metabolized < 20% by the liver (with a wide therapeutic index), or gaseous/volatile drugs eliminated primarily through the lungs. In these cases, a hepatic impairment study is unlikely to provide useful information. Drugs intended for single dose administration also do not typically require hepatic impairment studies, unless there is clinical concern that one might be needed.
Defining Liver Impairment
The FDA recommends that hepatic impairment be classified according to the Child-Pugh system, which assigns point values according to clinical and biochemical markers of liver function:
- serum bilirubin
- serum albumin
- prothrombin time
- encephalopathy grade
- presence/severity of ascites
Higher point values indicate more severe impairment, allowing classifications as mild (5-6), moderate (7-9), or severe (10-15) impairment.
Types of Studies
The FDA guidance includes three PK study types to evaluate hepatic impairment, including full, reduced, and population PK (popPK) based approaches.
Basic Full Study Design
This is the most comprehensive study design and allows for the development of specific dosing recommendations for each level of hepatic impairment. Individuals with normal liver function, mild impairment, moderate impairment, and severe impairment should be included in these studies, with at least six subjects in each group. For the full study design, as well as other types of hepatic impairment studies, it is important that the control group (i.e., those with normal hepatic function) be pulled from the intended patient population and not be young, healthy volunteers. In general, individuals with normal hepatic function should be matched with individuals with hepatic impairment using key demographic parameters including age, sex, race, and body weight or body mass index.
As the name suggests, these studies allow for a reduced number of evaluated groups. Reduced design studies can be designed in a number of different ways but often begin by comparing subjects with moderate hepatic impairment to subjects with normal hepatic function (at least 8 participants per group). Results in these individuals can then be used to inform dosing recommendations for other classifications. For example, if no effect on drug exposure is observed for individuals with moderate hepatic impairment versus individuals with normal hepatic function, then the label would indicate that no dosage adjustment is needed for individuals with mild or moderate hepatic impairment. If the drug is significantly cleared by the liver, then the label would urge caution for use in individuals with severe impairment.
Population PK-based approaches utilize data collected in Phase 2 and Phase 3 studies to analyze hepatic function as a covariate to describe impacts on PK. Like other designs, the popPK approach should include a preplanned analysis for hepatic impairment, evaluation of the severity of impairment (e.g., Child-Pugh classification), enough subjects spanning liver dysfunction ranges to detect PK differences, measurement of unbound drug concentrations (if appropriate), and measurement of parent drug as well as any active metabolites. Other study parameters, such as single versus multiple dosing and blood sampling schedules, will be dictated by the drug being studied.
Data Analysis and Labeling
Data analysis should determine the effect of hepatic impairment on PK parameters of the drug and any active metabolites. Important PK parameters include (as appropriate):
- Area under the concentration-time curve (AUC)
- Peak concentration (Cmax)
- Apparent oral clearance (CL/F)
- Renal and non-renal clearance
- Volume of distribution
- Terminal half-life (t1/2)
Compartmental or noncompartmental analysis can be used, as applicable. Results of the hepatic impairment study will be communicated in the product label. In cases of obvious effects (e.g., greater than ), dosing recommendations should be indicated. The label should also state if studies were conducted and no effect was found, if specific Child-Pugh groups were not studied, or if no studies were conducted. The FDA guidance provides some wording recommendations for the label, but the final label language will be established through negotiations between the Sponsor and the FDA prior to drug approval.
The PK of drugs that are processed by the liver can be substantially altered in individuals with diseases that result in liver impairment. Anticipating the need for a hepatic impairment study and implementing an appropriate study design will allow for a more efficient drug development program and a smoother path to approval. To learn more about strategies for assessing the effects of hepatic impairment on your product, connect with one of our senior consultants today.