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Updated: Jun 27, 2025

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
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Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics

Kit Wun Kathy Cheung1, Yang Tang2, Doreen Anders3

  • 1Clinical Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA.

Pharmaceutics
|April 27, 2024
PubMed

Insights

Pralsetinib pharmacokinetics were evaluated in patients with moderate to severe hepatic impairment. The study found no significant impact on drug exposure, suggesting no dose adjustment is needed for these patients.

Area of Science:

  • Pharmacology
  • Oncology
  • Clinical Pharmacology

Background:

  • Pralsetinib is a kinase inhibitor for metastatic RET fusion-positive non-small cell lung cancer.
  • Hepatic impairment (HI) may alter pralsetinib pharmacokinetics (PK) due to its primary hepatic elimination.
  • Mild HI showed minimal impact on pralsetinib PK.

Purpose of the Study:

  • To assess pralsetinib PK, safety, and tolerability in subjects with moderate and severe HI.
  • To compare pralsetinib exposure in subjects with HI versus those with normal hepatic function.

Main Methods:

  • PK, safety, and tolerability of pralsetinib were evaluated in subjects with moderate and severe HI.
  • Hepatic impairment was classified using Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria.
  • Systemic exposure (AUC0-∞) was compared between impaired and normal hepatic function groups.

Main Results:

  • Moderate and severe HI did not significantly alter pralsetinib systemic exposure (AUC0-∞).
  • Geometric mean ratios (GMR) for AUC0-∞ were comparable across different HI classifications and normal hepatic function.
  • AUC0-∞ GMRs ranged from 0.858 to 1.22 for moderate and severe HI compared to normal hepatic function.

Conclusions:

  • Moderate and severe hepatic impairment do not meaningfully impact pralsetinib exposure.
  • Dose adjustment of pralsetinib is not warranted in patients with moderate or severe hepatic impairment.
  • Pralsetinib can be safely administered without dose modification in patients with hepatic dysfunction.
Keywords:
hepatic impairmentpharmacokineticspralsetinib

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