Research and Development Strategies
The Benefits and Risks of Using Positron Emission Tomography in Clinical Drug Development
Julian C Matthews Senior Lecturer, Wolfson Molecular Imaging Centre, University of Manchester
Abstract
Owing to increasing costs and attrition in drug development, there is a great need for alternative approaches. Positron emission tomography (PET) is a molecular imaging technique that has the potential to provide information that can be used to predict the likely success or failure of a drug in late-stage development and optimise parameters, such as dose, dosing schedule and drug formulation. The technique is complex and expensive, however, owing to the use of short-lived isotopes and the requirements of regulators in radiotracer production. It is therefore important that the benefits and risks of PET studies within drug development are understood and assessed in order that such studies provide value. This article describes the technology and logistics of performing PET scanning and assesses the benefits and risks of performing three types of PET study: biodistribution, receptor occupancy and pharmacodynamic investigations.
Keywords Positron emission tomography, drug development, biodistribution, receptor occupancy, pharmacodynamic response
Disclosure: The author has no conflicts of interest to declare. Acknowledgements: The [18F]5-fluorouracil data were collected at the Medical Research Council (MRC) cyclotron unit in Hammersmith, London by Robert Harte and Pat Price (PI). The [11C]DASB data were collected at the Wolfson Molecular Imaging Centre, Manchester with Peter Talbot (PI) and in collaboration with ICON Development Solutions. Received: 4 July 2010 Accepted: 13 November 2010 Citation: Drug Development, 2010;5:37–42 Correspondence: Julian C Matthews, School of Cancer and Enabling Sciences, Wolfson Molecular Imaging Centre, MAHSC, University of Manchester, Manchester, UK. E:
julian.matthews@
manchester.ac.uk
Over the last decade or more, the cost of drug development has been ever-increasing, with additional studies often required in order to satisfy the demands of regulators. In addition to this, the failure rate of drugs in clinical development is high. Consequently, there is a pressing need for alternative approaches to drug development that provide predictive information early on regarding the likely success or failure of a drug, optimisation of parameters (such as dose, dosing schedule and drug formulation) and speed up development timelines.
Positron emission tomography (PET) is a molecular imaging technique that has the potential to provide such information. The technique is complex and expensive, however, owing to the use of short-lived isotopes and the demands of regulators in the manufacture of radiotracers. In addition, the work-up of radiolabelling methods and regulatory approval has the potential to create significant lead times in the setting up of such studies. It is therefore critical that the benefits and risks of PET studies within the drug development plan are understood and assessed so that such studies provide value. It is also important to understand the processes and logistical aspects of setting up clinical trials involving PET imaging. This article will present a number of types of study that can be performed using PET imaging: biodistribution studies, occupancy studies and pharmacodynamic (PD) response studies. For each type of study, the benefits and risks will be discussed.
Positron Emission Tomography Imaging At the heart of PET imaging are positron-emitting isotopes. These usually short-lived isotopes (see Table 1) with half-lives that typically
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range from two minutes to two hours, although longer-lived isotopes do exist.
Importantly, with isotopes of nitrogen, carbon, oxygen and fluorine, numerous organic molecules including drugs can be labelled without altering the chemical form of the molecule. The isotopes are typically produced using a cyclotron, which owing to the short half-life needs to be located on the imaging site or within a short car journey for longer-lived isotopes such as fluorine-18.
Following isotope production, rapid radiosynthesis, purification and formulation is required. Owing to the high levels of radioactivity required at the start of production, specialised hot cell equipment with remote robotic radiochemistry is required. In order to ensure patient safety, a series of rapid quality-control tests need to be performed prior to administration. All of these tests must be completed while the radiotracer is decaying. This entire process needs to be performed to good medical practice (GMP) standards, with regulatory oversight and approval.
Prior to starting a study, a number of logistical and regulatory hurdles need to be crossed. For sites that do not already have their production qualified to GMP standards for the radiotracer of interest, the radiosynthesis will first need to be developed, optimised and validated. For molecules not previously labelled with positron-emitting isotopes, there is variable and potentially considerable risk involved, with significant challenges for the radio-chemist to overcome. Even for
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