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How to Avoid a Hepatic Impairment Clinical Study During Drug Development

Is it possible to avoid a hepatic impairment clinical study during drug development? The short answer is ‘yes,’ by using a population pharmacokinetic (PK) and modeling approach.

A Brief Introduction to Hepatic Impairments Studies

Because of the crucial role of the liver in drug metabolism, it is often necessary to consider the effect of hepatic impairment on drug exposure and safety to help guide dosing recommendations for physicians in clinical practice. These investigations typically involve enrolling patients with varying degrees of hepatic impairment to determine the effects of impaired liver function on the concentration of the drug (and/or key metabolites) in plasma. It should be noted that enrolling patients with severe hepatic impairment can be very challenging.

Traditionally, these data are generated within the context of a standalone hepatic impairment study. To this end, the FDA has provided some helpful guidance on study design and data analysis for these studies in their Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function. The hepatic impairment study recommendations from the FDA call for determining the Child-Pugh score for hepatic dysfunction. Based upon the total Child-Pugh score, hepatic impairment is classified as mild (Class A), moderate (Class B), or severe (Class C).

But what if there were a way to collect these data within the context of other studies that you have already planned to run, without having to conduct a completely independent hepatic impairment study?

Avoiding Standalone Studies

Before we get too far along, the first thing you need to ask is whether a hepatic impairment study is required for your product. The FDA recommends a PK study in patients with impaired hepatic function if hepatic metabolism and/or excretion accounts for a substantial portion (>20% of the absorbed drug) of the elimination of a parent drug or active metabolite.

For better or worse, this is almost always the case. So, some sort of investigation into the effect of hepatic impairment will be needed unless hepatically impaired patients are to be excluded in the drug label.

Fortunately, it may be possible to gather the needed data while avoiding a standalone hepatic impairment study by using modeling and simulation-based approaches coupled with thoughtful clinical study design in phase 2 and phase 3.

From a design standpoint, the key parameters that need to be collected to compute the Child-Pugh score include the following:

  • Total Bilirubin
  • Serum Albumin
  • International Normalized Ratio (INR, a measure of coagulation)
  • Ascites (fluid accumulation in the abdominal cavity)
  • Hepatic Encephalopathy (neuropsychiatric abnormalities resulting from liver dysfunction)

Prospectively planning for phase 2 and phase 3 clinical studies to capture these data parameters is relatively easy to do. Three of the parameters used to compute the Child-Pugh score are laboratory values that can be added to the standard panel collected during a planned study. The assessment of ascites and hepatic encephalopathy can be added to the standard physical exam with appropriate investigational site training.

Using pooled, cross-study data collected during phases 2 and 3, population pharmacokinetics modeling can be employed to understand the impact of hepatic impairment on drug exposure and safety.

Caveats and Considerations

It is important to note that this streamlined approach is not for every drug program, so prospective clinical pharmacology planning to determine the feasibility and cost-effectiveness for your specific program is important. We recognize that most phase 2 and phase 3 programs exclude patients with severe liver disease. However, the potential value of including patients with moderate liver disease (perhaps just a small number with Child-Pugh class B impairment) in phase 2 and phase 3 studies should be considered.

Even if patients with hepatic impairment are specifically excluded in clinical studies based on inclusion/exclusion criteria, some patient populations may drift in their hepatic function over time. Depending on the length of the planned phase 2 or phase 3 studies, it is possible that some degree of variability in hepatic function could be observed in the study.

Also, some indications are enriched with patients that have varying degrees of hepatic function. In any given population, it is reasonable to expect multiple individuals to present with Child-Pugh Class A (mild) hepatic impairment and possibly some with Child-Pugh Class B (moderate) hepatic impairment.

Implementation of a model-based hepatic impairment evaluation should be considered early in your development planning (ideally prior to entering phase 2) …we will address clinical pharmacology planning in a future blog post.

Of note, similar strategies are also possible for avoiding other standalone clinical pharmacology studies. For example, you may be able to avoid Thorough QT studies by enriching already-planned studies with electrocardiograms matched with pharmacokinetics data to allow for concentration-QT analysis. Renal impairment assessments can also benefit from this type of approach.


Thoughtful study design, such as including the assessment of the five key parameters for determining Child-Pugh score within your phase 2 and 3 studies, may help you avoid a standalone hepatic impairment study.

Consideration of population pharmacokinetic analysis on pooled data from multiple studies can provide critical insight into the effect of hepatic impairment on drug pharmacokinetics and dosing.

Both study design and analytical considerations are central to an efficient and cohesive clinical pharmacology strategy. Leveraging these strategies can help speed your program toward approval and reduce development costs.

There are almost always more possibilities to streamline your program and potentially reduce your time to market. Let us show you how the Nuventra team can help.
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