Pharmacokinetic drug evaluation of ribociclib for the treatment of metastatic, hormone-positive breast cancer.

Abstract

INTRODUCTION:

Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). Ribociclib is an orally bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub-micromolar concentrations in a variety of pRb-positive cancer cells in vitro. Ribociclib is a new standard of care for metastatic HR+/HER2 negative metastatic breast cancer. Area covered: In this article, we review the preclinical and clinical development of ribociclib as well as discussing the role for novel applications of these agents outside the arena of HR-positive, HER2-negative advanced breast cancer. Expert opinion: Results of pivotal phase II and III trials investigating ribociclib in patients with advanced-stage (HR)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a safe toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge and might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response. The use of combination therapies to optimize CDK4/6 targeting is under development.

• Authors: Giuseppe Curigliano, Carmen Criscitiello, Angela Esposito, Mattia Intra, Saverio Minucci
• Journal: Expert opinion on drug metabolism & toxicology (Expert Opin Drug Metab Toxicol) Vol. 13 Issue 5 Pg. 575-581 (May 2017) ISSN: 1744-7607 [Electronic] England
• PMID: 28395543 (Publication Type: Journal Article, Review)

Chemical References

• Aminopyridines
• Antineoplastic Agents
• Purines
• Receptor, ErbB-2
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• ribociclib

Topics

• Aminopyridines (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Breast Neoplasms (drug therapy, pathology)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Female
• Humans
• Neoplasm Metastasis
• Purines (administration & dosage, adverse effects, pharmacokinetics)
• Receptor, ErbB-2 (metabolism)