The role of functional and molecular imaging in cancer drug discovery and development.
Studies of pharmacokinetics (which is what the body does to the drug) and pharmacodynamics (which is what the drug does to the body) are essential components of the modern process of cancer drug discovery and development. Defining the precise relationship between pharmacokinetics and pharmacodynamics is critical. It is especially important to establish a well understood pharmacological "audit trail" that links together all of the essential parameters of drug action, from the molecular target to the clinical effects. The pharmacological audit trail allows us to answer two absolutely crucial questions: (1) how much gets there; and (2) what does it do? During the pre-clinical drug discovery phase, it is essential that pharmacokinetic/pharmacodynamic (PK/PD) properties are optimized, so that the best candidate can be selected for clinical development. As part of contemporary mechanistic, hypothesis-testing clinical trials, construction of the pharmacological PK/PD audit trail facilitates rational decision-making. However, PK/PD endpoints frequently require invasive sampling of body fluids and tissues. Non-invasive molecular measurements, e.g. using MRI or spectroscopy, or positron emission tomography, are therefore very attractive. This review highlights the need for PK/PD endpoints in modern drug design and development, illustrates the value of PK/PD endpoints, and emphasises the importance of non-invasive molecular imaging in drug development. Examples cited include the use of PK/PD endpoints in the development of molecular therapeutic drugs such as the Hsp90 molecular chaperone inhibitor 17AAG, as well as the development of SR-4554 as a non-invasive probe for the detection of tumour hypoxia.
Seddon
B M
BM
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Workman
P
P
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones; D003952:Diagnostic Imaging / Q000379:methods*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D047029:Lactams, Macrocyclic; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009593:Nitroimidazoles; D049268:Positron-Emission Tomography / Q000379:methods; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013678:Technology, Pharmaceutical / Q000379:methods; D014463:Ultrasonography / Q000379:methods
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009593:Nitroimidazoles; D017828:Rifabutin; C112765:tanespimycin; C095171:SR 4554