Sabina Paglialunga, PhD1; Natacha Benrimoh, MSc2; Angela Choi, PhD2; Aernout van Haarst, PhD1 Â
1. Scientific Affairs, Celerion; 2. Data Management and Biometrics.
After a long awaited 23 years, the FDA has updated their thinking on hepatic impairment pharmacokinetic (PK) studies. The new draft guidance reflects more than 20 years of clinical pharmacology advances and broadens applicability beyond traditional small molecules. That said, there are some important recommendations drug sponsors should be aware of.
We’ve summarized the 5 key updated guidance recommendations that will impact your next dedicated hepatic impairment PK study:
- Expanding Drug Modalities for Hepatic Impairment PK Studies
The draft guidance acknowledges that therapeutic peptides, proteins and even monoclonal antibodies as well as antibody-drug conjugates have shown altered PK in patients with hepatic impairment, and therefore a dedicated study should be considered during their development. Moreover, the FDA encourages a dedicated study to be conducted during early drug development to adequately guide late phase trial eligibility.
Key takeaway: Biologics are no longer exempt from conducting a hepatic impairment PK study.
- When a Hepatic Impairment Study is Recommended
Whereas the previous 2003 draft guidance provided a limited set of conditions when a dedicated PK study was recommended, the new 2026 draft guidance expands on this and introduces several new criteria:
- Hepatic metabolism/excretion >30% of elimination
- Narrow exposure margins where small PK changes matter
- When the elimination pathways are not well characterized
- Drug intended for liver disease
- Drug likely to be used in patients with hepatic impairment
Key takeaway: The criteria for conducting a dedicated study has expanded and most study drugs in development will fall into one or more of these buckets. Drug sponsors may want to consider including a hepatic impairment study in their drug program development plan.
- Detailed Participant Characterization
The Child-Pugh (CP) classification system is the preferred score for categorizing participant hepatic impairment. The new guidance recommends reporting both the total and component-level CP scores. Also, the FDA urges to report the etiology of underlying liver disease as well as assess confounding effects influencing the CP score, such as the presence of vitamin K deficiency, Gilbert syndrome, and IV fluid or anticoagulant administration. In such cases, CP scoring should be avoided.
The new guidance also places greater emphasis on the role of pharmacogenomics, and when relevant CYP/transporter genotyping is recommended.
Key takeaway: Greater participant characterization at the level of their liver disease etiology, factors affecting the CP score and genotype may either minimize or at least help explain potential variability in PK results.
- Major Changes to Study Design
The new draft guidance recommends a full study design, covering the spectrum of liver disease including participants with mild, moderate, and severe hepatic impairment compared to matched controls. In certain cases, the study design may include patients with severe hepatic impairment vs controls. This is a significant departure from the previous guidance, which proposed moderate hepatic impairment for a reduced design.
In line with the 2024 renal impairment guidance, now sample size justification is required. Based on the study drug coefficient of variability (%CV), the sample size for a hepatic impairment PK study could range from 6-12 (or more!) participants per cohort (i.e. severity group).
Key takeaway: The recent guidance will place a greater demand on the severe hepatic impairment pool of participants, which may impact study timelines, number of clinical sites and overall study costs.
- Need for Additional Sample Collection and Storage
It is well recognized that plasma proteins can be altered in patients with liver disease.  Therefore, when a study drug is extensively bound to plasma protein, defined in the guidance as fraction unbound is <10%, the sponsor should determine the unbound fraction at trough (Cmin) and maximum plasma concentration (Cmax). For PK analysis, total and unbound (free) drug concentrations should be reported. Importantly, the new guidance adds that for study drugs that are not extensively bound to plasma proteins, the sponsor should retain and archive samples to allow for future assessment to explain unexpected observations.
Key takeaway: Blood sample collection for protein binding will be required for most studies, whether this should be analyzed right away or stored will depend on the study drug characteristics.
Putting It All Together
The new draft guidance reflects the modernization of clinical pharmacology, current technologies, and more robust participant and PK characterization to support safe drug use in patients with liver disease. While these updates are welcome, they also add complexity to dedicated hepatic impairment study design. Partnering with an experienced CRO like Celerion, with decades of expertise in hepatic impairment study design, protocol development, and study management, can help sponsors navigate these recommendations efficiently. In addition, Celerion’s robust site network provides access to nearly 2000 patients with hepatic impairment across the US and EU to support study recruitment under the new guidance.