PET for in vivo pharmacokinetic and pharmacodynamic measurements

Abstract

Positron emission tomography (PET) scanning is evolving as a unique tool for drug development in oncology for improving both the efficacy of established treatment and in evaluating novel anticancer agents. As a non-invasive functional imaging modality, PET has an unrivalled sensitivity when monitoring the pharmacokinetics and pharmacodynamics of drugs and biochemicals when radiolabelled with short living positron-emitting radioisotopes. This is of particular relevance in assessing newer molecular-targeted therapy where conventional evaluation criteria (maximum tolerated dose and tumour shrinkage for example) may be inappropriate. PET has already been applied to a wide number of drugs to demonstrate activity in vivo from standard chemotherapy such as 5-fluorouracil (5-FU) [J Clin Oncol 17 (1999) 1580], to novel molecular agents such as those involved in tumour angiogenesis [Br J Cancer 83 (2000) P6] and antivascular therapy [Proc Annu Meet Am Soc Clin Oncol 19 (2000) 179a]. This review will evaluate the achievements of PET in the drug development process, an approach that promises to facilitate the rapid translation of scientific research into current clinical practice.

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.