Clinical Pharmacology and Side Effects of Venetoclax in Hematologic Malignancies.

in Current drug metabolism by Yuting Yan, Yujiao Guo, Ziyi Wang, Wei He, Yu Zhu, Xiaoli Zhao, Luning Sun, Yongqing Wang

TLDR

  • Venetoclax is a BCL-2 inhibitor used to treat hematological neoplasms, with significant clinical pharmacology implications for its use in patients with compromised hepatic function and those receiving concomitant medications.
  • Further research is needed to optimize dosing and improve patient outcomes, particularly regarding exposure-response relationships and adverse events.

Abstract

Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.

Overview

  • The study focuses on the clinical pharmacology of venetoclax, a BCL-2 inhibitor, and its effects on patients with hematological neoplasms.
  • The study investigates the pharmacokinetic properties of venetoclax, including its absorption, distribution, metabolism, and excretion, as well as its potential interactions with other medications.
  • The primary objective of the study is to summarize the current clinical pharmacology studies and side effects of venetoclax, with the aim of informing its use in clinical practice.

Comparative Analysis & Findings

  • Pharmacokinetic studies revealed that venetoclax has a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL.
  • Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment influence venetoclax dose selection.
  • Clinical medication interaction studies indicate that venetoclax is a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, and that dose modifications are necessary when co-administered with strong CYP3A inhibitors.

Implications and Future Directions

  • The findings of this study have significant implications for the clinical use of venetoclax, particularly in patients with compromised hepatic function and those receiving concomitant medications.
  • Future studies should aim to investigate the optimal dosing of venetoclax for different patient populations, including those with varying degrees of hepatic impairment and those receiving comorbid medications.
  • Further research is also needed to better understand the exposure-response relationship of venetoclax and its correlation with adverse events, particularly neutropenia and cardiac toxicity.
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