The effect of liver dysfunction on the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers

• Published in: Cancer chemotherapy and pharmacology Vol. 94; no. 2; pp. 157 - 167
• Main Authors: Dunn, Allison, Takebe, Naoko, Chen, Alice, Kummar, Shivaani, Piekarz, Richard, Kiesel, Brian, Moore, Nancy, Doroshow, James, Beumer, Jan H., Gobburu, Jogarao V. S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2024; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; biochemical pathways; Cancer Research; Female; Hepatocytes; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - pharmacokinetics; liver; Liver diseases; Liver Diseases - metabolism; Lymphocytes T; Male; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Metabolic pathways; Metabolism; Metabolites; Middle Aged; Models, Biological; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Original Article; patients; Pharmacokinetics; Pharmacology/Toxicology; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; T-cell lymphoma; Population pharmacokinetics; Belinostat; Parent-metabolite modeling
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-024-04651-x

Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system. The final model was then implemented to assess the effect of liver impairment on each metabolic pathway of belinostat. It was determined that significant pharmacokinetic differences could only be demonstrated in patients with severe hepatic impairment. The final model estimated a 35%–47% reduction in metabolic clearance attributed to UGT1A1/2B7 glucuronidation, CYP2A6/3A4/2C9 metabolism, and β-oxidation. These hepatic impairment effects reduced between-subject variability by only 5%–8% for their respective parameter, with a large amount of remaining unexplained variability. With further validation, this model can be leveraged to assess the need for dose adjustments in this patient population.