PET for in vivo pharmacokinetic and pharmacodynamic measurements
Introduction
The field of oncology has undergone a revolution in drug discovery and therapeutic approaches led primarily through an increased understanding of genetic and molecular mechanisms in cancer evolution. Correspondingly, the previously held empirical random screening method in oncological drug development is being gradually replaced with the concept of rational drug design. This process identifies specific targets responsible for malignant cellular transformation and more importantly, drugs that can overcome them, rather than simply using the antiproliferative activity of a drug as an endpoint. New agents discovered for possible use as anticancer therapy include genes, proteins, growth factors and receptors, and those involved in specific pathways, for example, angiogenesis, signal transduction, cell cycle, cell apoptosis, invasion, metastasis, drug resistance and blood flow. Further expansion of drug development has resulted from combinatorial chemistry, another new technology that has grown at a tremendous rate to produce a plethora of novel therapeutic targets [4]. However, drug development is still a protracted and expensive business. It is estimated that of 5000 possible drugs screened, only one drug is successfully approved and introduced into the market [5]. In addition, the candidate drug finally selected takes an average of 10 years of development and requires an investment of several million pounds before eventually proceeding to clinical trial [6]. Consequently, there is a need for an additional method of evaluating potential new drugs and to optimise existing treatment strategies. There is an increasing realisation that radiotracer drug imaging as used in positron emission tomography (PET) has a major role to play in expediting drug development both in the clinical and preclinical setting, and which may in addition reduce the substantial costs currently incurred.
The objectives of drug development in oncology are clearly defined. The aims involve the determination of optimum delivery of drug to the site of the tumour with minimum exposure to normal tissue, thereby achieving maximum therapeutic benefit. This requires accurate monitoring of drug pharmacology including pharmacokinetics (absorption, distribution, metabolism and elimination) and pharmacodynamics (tumour response, enzyme induction/inhibition receptor binding, tolerance, etc.). At present, these parameters are measured by analysis of blood and urine samples and occasionally using biopsy specimens of relevant tissues. Whilst this strategy is suitable for certain anticancer drugs, plasma monitoring may be irrelevant with the next generation of therapies such as anti-angiogenesis, where treatment is designed to target specific tissues. In this situation, the availability of a positron emitting radiotracer to quantitate drug delivery and response in the relevant tissue can significantly advance our knowledge of drug pharmacology. The ability of PET to meet the challenges and demands of drug development relies on a multidisciplinary team consisting of radiochemists, biologists, mathematical modellers, pharmacologists and clinicians.
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Radiotracers
There are many positron emitting isotopes available for commonly occurring elements including carbon, oxygen, nitrogen and fluorine with half-lives ranging from seconds to several days (Table 1). They are usually made in a cyclotron, although some (copper 62) can be manufactured in a nuclear generator. Radiotracers are produced after replacement of a molecule in a compound of interest with a radionuclide without modifying their pharmaceutical, biological or biochemical properties. For example,
Acquisition and modelling of PET images
A 3D image of the distribution of the radiolabelled drug within the body comes from the simultaneous detection of two gamma rays from the decay of the positron emitting radionuclide. The two 511 keV gamma rays are emitted at approximately 180° and are each recorded coincidentally by rings of external nuclear detectors, with the inference that the decay event occurred between the opposing two detectors. Data are obtained as sinograms that are reconstructed into tomographic images after
PET and drug evaluation
There are a number of generic issues in drug development that can be addressed by PET imaging. These can be described in the form of questions: (1) does the drug sufficiently distribute to target (tumour) and how much goes to normal tissue, where toxicity may be produced, (2) how is the drug eliminated from tumour and normal tissue, (3) does the drug modulate its target in a predictable way, (4) is the drug efficacious. Points (1) and (2) can be classified as pharmacokinetic studies, and (3)
Summary
Advances in technology have made in vivo assessment of physiological and biochemical processes in humans a reality. This has been achieved by the integrated work of a multidisciplinary team within a PET department. PET is an invaluable tool in the preclinical assessment of drugs prior to further development. Clinical assessment of drugs can help elucidate mechanisms of action, and resistance, at tracer doses. Newer therapies can be investigated where conventional methods of drug analysis will
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