Abstract

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.

中文翻译：

---

肝功能障碍对晚期癌症患者贝利司他及其五种代谢物药代动力学分布的影响

摘要

Belinostat 于 2014 年被批准用于治疗复发或难治性外周 T 细胞淋巴瘤，但没有足够的数据来推荐中度至重度肝功能不全患者的剂量。该分析的目的是表征贝利司他及其五种代谢物在晚期癌症和不同程度肝功能障碍患者中的​​药代动力学分布。因此，开发了群体药代动力学模型来描述母体代谢物系统。然后应用最终模型来评估肝损伤对贝利司他每个代谢途径的影响。据确定，只有在患有严重肝功能损害的患者中才能表现出显着的药代动力学差异。最终模型估计，UGT1A1/2B7 葡萄糖醛酸化、CYP2A6/3A4/2C9 代谢和 β-氧化导致代谢清除率降低 35%–47%。这些肝损伤效应仅将受试者之间各自参数的变异性降低了 5%–8%，还存在大量无法解释的变异性。通过进一步验证，可以利用该模型来评估该患者群体中剂量调整的需要。