Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism.

Jinhai Wang,Ying Fang,R Andrea Fan,Christopher J Kirk

doi:10.3390/ijms222111595

Abstract

The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.

Highlights

The ubiquitin/proteasome system constitutes one of the primary means by which intracellular proteins are degraded
We summarize the metabolism, pharmacokinetics, and pharmacodynamics of the three clinically-approved proteasome inhibitors and compare those profiles across chemical classes
IV administration of carfilzomib resulted in suppression of proteasome CT-L activity in patients when measured in blood one hour after the first dose

Summary

Introduction

The ubiquitin/proteasome system constitutes one of the primary means by which intracellular proteins are degraded. 2021, 22, x FOR PEER RCEYVPIE3WA4 inhibitor, revealed an increase in bortezomib exposure by 1.4-fold [44], fu6 rotfhe19r indicating the role of CYP3A4 in the metabolism of this drug. In clinical studies using IV administration, proteasome inhibition in whole blood samples was rapid and dose-dependent and recovered within 24 h dosing [45].

Results

Conclusion