Generally, a clinical pharmacology study is required in subjects with hepatic impairment if a drug’s hepatic metabolism and/or excretion accounts for more than 20% of the elimination of a parent drug or active metabolite. Hepatic impairment clinical studies are typically needed in an NDA submission for drugs with a narrow therapeutic range or if the routes of metabolism and excretion of a drug are unknown.
What is Hepatic Impairment?
“Hepatic” is associated with the liver. The liver is a major organ involved in the clearance of drugs. Drugs are cleared by a variety of mechanisms and pathways. Hepatic impairment, dysfunction, and disease can be either acute or chronic and can alter the clearance of drugs from the body.
Acute liver failure happens fast and can be caused by overdose, poisoning, or certain autoimmune diseases. Chronic liver failure develops slowly and causes inflammation. Patients with hepatic impairment or disease may require modification to their dosing regimen compared to patients with normal hepatic function. The impact of hepatic impairment on a drug’s disposition, clearance, and metabolism is assessed by pharmacokinetics (PK).
Considerations for Hepatic Impairment Studies
There are many factors and exceptions to consider when determining the proper strategy for collecting hepatic impairment PK data. A drug may need to be evaluated by a standalone hepatic impairment clinical study.
For some drugs, hepatic impairment can be evaluated within the context of late phase studies by using a population PK modeling and sparse sampling approach in a patient population enriched with varying degrees of hepatic disease. When a population PK modeling approach is feasible, it is possible to avoid a standalone hepatic impairment clinical study. Alternatively, in some cases, hepatic impairment evaluation will not be necessary or required at all.
Full PK Study Design Considerations
The FDA’s guidance on PK in patients with impaired hepatic function suggests that a full PK study can be conducted in patients from the three Child-Pugh categories of impaired hepatic function as well as matched controls (i.e., matched to age, weight, and gender). The three Child-Pugh categories are:
- Child-Pugh A: Mild
- Child-Pugh B: Moderate
- Child-Pugh C: Severe
Enrolling severe patients from Child-Pugh class C can be difficult and time-consuming. Nuventra has clinical and regulatory strategies for efficiently executing this type of study. The overall goal is to determine whether the PK and/or PD of a drug and its active metabolites are altered in patients with hepatic impairment.
Reduced PK Study Design Considerations
In a reduced PK study design, only subjects with moderate hepatic impairment (Child-Pugh class B) are enrolled and compared to matched healthy volunteers. At least eight evaluable subjects each from moderate impairment and control groups should be enrolled for the reduced PK study. Statistical power calculations may be needed depending on the anticipated variability in the PK of the drug.
The reduced and full PK study designs can be conducted either as single dose or multiple dose studies depending on the expected PK behavior of the drug. Also, dose strength must be considered in these studies since impaired hepatic function might lead to higher exposures and safety concerns for the study population. As such, a unique PK plasma sampling schedule for the different levels of hepatic impairment might need to be considered.
An experienced pharmacokineticist can quickly and efficiently determine if any dose adjustments are needed in a hepatic impairment study and also advise on the frequency of plasma sample collection to enable a robust PK assessment.
Population PK Analyses for Hepatic Impairment
Population PK analysis is conducted with sparse sampling of drug concentrations from patients enrolled in late-stage studies. The studies need to include patients with varying degrees of hepatic impairment to model the relationship between the Child-Pugh score and PK parameters (such as AUC, Cmax, apparent clearance (CL/F), apparent volume of distribution (V/F), terminal half-life (t1/2), and more). To enable a robust population PK analysis, sponsors must take care to capture individual components of the Child-Pugh score including encephalopathy, ascites, serum bilirubin, serum albumin, and prothrombin time.
When to Execute Hepatic Impairment Studies
Conducting a full or reduced hepatic impairment study depends on a number of factors including in vitro CYP P450 inhibition/induction assays and the potential for the investigational drug to have altered PK in patients with hepatic impairment. If a drug has a low potential for altered PK with hepatic impairment or will never be used in patients with severe hepatic disease then a reduced study design in moderate hepatic disease may be more appropriate.
Alternatively, if the late-stage studies will be enriched for varying degrees of hepatic dysfunction then population PK analyses could be conducted, which may be more cost-effective relative to standalone hepatic impairment PK studies.
Hepatic Impairment Study Experience
There are almost always more possibilities to streamline your program and potentially avoid conducting a hepatic impairment study by using a population PK modeling and simulation approach. Nuventra has significant experience designing studies for patients with liver disease and hepatic encephalopathy to enable a successful hepatic impairment clinical study and/or a population PK analysis.
Contact us to find out if a full or reduced hepatic impairment study is required for your program and if you can avoid a hepatic impairment study completely with existing data. Explore all of our clinical pharmacology and drug development consulting services.