Use of Pharmacokinetic/Pharmacodynamic Biomarkers to Support Rational Cancer Drug Development

Abstract

The process of drug development in oncology has struggled to alter at a pace in keeping with the rapid discovery and testing of agents that act on a wide variety of molecular targets. The rational development of such agents requires an understanding of drug effect(s) on their purported target. It is likely that testing these drugs in a framework designed to examine cytotoxic agents will fail to establish their full potential. We discuss how data gained from biomarker investigation might impact on drug development and provide examples that highlight the development, validation and use of pharmacokinetic, and especially pharmacodynamic biomarkers as drug development moves from the laboratory into clinical testing. The challenges of performing assays to satisfy regulatory requirements have been the subject of much debate. We recommend the implementation of appropriate, fit-for-purpose biomarkers in clinical trials of all new cancer drugs.

Keywords: :

• antineoplastic agents
• biomarkers
• drug development
• drug therapy
• molecular diagnostic techniques
• neoplasms
• pharmacodynamics
• pharmacokinetics
• pharmacology
• research
• signal transduction
• therapeutics

Financial & competing interests disclosure

PI3K inhibitors have been developed in the Centre in collaboration with, and with research funding from, Astellas (formerly Yamanouchi) and Piramed, and are licensed to Genentech. PW is a founder of, consultant to, and stockholder in PIramed. Heat shock protein 90 inhibitors have been developed in the Centre in collaboration with, and with research funding from, Vernalis (formerly RiboTargets) and are licensed to Novartis. PW is a consultant to Novartis. CDK inhibitors have been developed in the Centre in collaboration with, and with research funding from, Cyclacel.

Work in the authors‘ laboratory is funded by Cancer Research UK [CUK] Programme Grant Numbers C309/A2187 and C309/A8274. PW is a Cancer Research UK Life Fellow and DS and SP are Cancer Research UK Clinical Fellows. We thank many colleagues and collaborators for helpful discussions. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

Hsp: Heat shock protein; PBMC: Peripheral blood mononuclear cells; SOP: Standard operating procedure.

Definitions of terms taken from [122].

Additional information

Funding

PI3K inhibitors have been developed in the Centre in collaboration with, and with research funding from, Astellas (formerly Yamanouchi) and Piramed, and are licensed to Genentech. PW is a founder of, consultant to, and stockholder in PIramed. Heat shock protein 90 inhibitors have been developed in the Centre in collaboration with, and with research funding from, Vernalis (formerly RiboTargets) and are licensed to Novartis. PW is a consultant to Novartis. CDK inhibitors have been developed in the Centre in collaboration with, and with research funding from, Cyclacel.