© The Author 2006. Published by Oxford University Press.
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Minimally Invasive Pharmacokinetic and Pharmacodynamic Technologies in Hypothesis-Testing Clinical Trials of Innovative Therapies
For the Cancer Research UK Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee
Affiliations of authors: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, U.K. (PW); Imperial College London, Faculty of Medicine, London, U.K. (EOA); Cancer Research UK Biomedical Magnetic Resonance Research Group, St. George's Hospital Medical School, London, U.K. (YLC, JRG); Cancer Research UK Drug Development Office, London, U.K. (RH); Cancer Research UK Clinical Magnetic Resonance Research Group, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, U.K. (MOL); Gray Cancer Institute, Mount Vernon Hospital, Middlesex, U.K. (RJM); Novartis Institute for Biomedical Research, Basel, Switzerland (PMJM); Cancer Research UK PET Oncology Group, Molecular Imaging Centre, Manchester, U.K. (PMP); Cancer Research UK/University of Manchester Radiochemical Targeting & Imaging Group, Paterson Institute of Cancer Research, Manchester, U.K. (JZ)
Correspondence to: Paul Workman, PhD, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, United Kingdom (e-mail: paul.workman{at}icr.ac.uk).
Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.
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