079: Exploring the Impact of Hepatic Impairment on the Pharmacokinetics of New Molecular Entities: A Comprehensive Analysis of Labeling Information

Statement of Purpose, Innovation or Hypothesis: Regulatory agencies often require sponsors to address dosing recommendations in patients with various degrees of hepatic impairment (HI). To date, dosing recommendations in patients with HI have been informed by dedicated pharmacokinetic (PK) studies in participants with HI, population PK analysis (popPK), and prediction based on the mechanism of action or route of metabolism. We sought to analyze HI labeling information of FDA-approved-new molecular entities (NMEs) available upon approval. The aim of the study was to characterize the current approaches used to inform dosing in patients with HI and the type of dosing recommendations available at the time of approval.

Description of Methods & Materials: We collected HI related labeling information for FDA-approved NMEs from 2019 to 2023 available at drugs@FDA (Drugs@FDA: FDA-Approved Drugs). Information collected included: the presence of labeling language related to dosing patients with HI, type of information used to inform labeling, presence of exposure changes due to HI, type of dosing recommendations in mild, moderate and severe HI, and labeling updates related to HI since the time of approval.

Data & Results: Out of 171 approved NMEs, 140 (82%) mentioned HI in the labeling at the time of initial approval including 13 indicating that the effect of HI was not evaluated. Among the remaining 127 NMEs, 88 (69%) clearly mentioned the source of dosing recommendations in the labeling. Dosing recommendations were based on a dedicated HI study (n=72, 57%), popPK (n=25, 20%), prediction (n=15, 12%), combination of multiple sources (n=8, 6%) including two cases using physiologically-based PK (PBPK) modeling, or other sources (n=7, 6%). Among the 127 labelings with HI dosing recommendations, 94% provided guidance for mild HI, 79% for moderate HI, and 59% for severe HI. Approximately 85% of mild, 47% of moderate, and 13% of severe HI recommendations suggested no dose adjustment. Nineteen out of 171 NMEs included post approval changes to the HI labeling language, either by adding a new category (12/19), revising prior recommendations (5/19) or other (2/19).

Interpretation, Conclusion or Significance: The majority of FDA-approved NMEs at the time of approval provided initial dosing recommendations for patients with HI; however, these recommendations were primarily available for mild HI and often suggested no dose adjustment. Gaps still exist in the HI labeling information especially for moderate and severe HI. Additionally, despite the advancements in PBPK modeling, its use in informing HI dosing remains minimal.

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