TY - JOUR
T1 - The effect of liver dysfunction on the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers
AU - Dunn, Allison
AU - Takebe, Naoko
AU - Chen, Alice
AU - Kummar, Shivaani
AU - Piekarz, Richard
AU - Kiesel, Brian
AU - Moore, Nancy
AU - Doroshow, James
AU - Beumer, Jan H.
AU - Gobburu, Jogarao V.S.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Belinostat
KW - Parent-metabolite modeling
KW - Population pharmacokinetics
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U2 - 10.1007/s00280-024-04651-x
DO - 10.1007/s00280-024-04651-x
M3 - Article
AN - SCOPUS:85187654026
SN - 0344-5704
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
ER -