The Benefits and Risks of Using Positron Emission Tomography in Clinical Drug Development


high SERT signal is normally observed. Despite this, an apparently normal signal was observed in the brainstem, in which 35% of the binding was displaced following sibutramine administration. This apparently atypical physiology may explain the lack of response observed for this individual with the PD model, despite good SERT occupancy within the brainstem.


The above example shows the potential utility of PET occupancy studies. Unlike biodistribution studies, measurements relate to the interaction at the site of action. Hence the results of these studies are more valuable in assessing likely efficacy, which can be related to upstream PK measurements and downstream PD measurements. Such studies can be used to optimise dosing regimens through investigation into the degree and longevity of occupancy following a dose or motivate drug reformation, should less than desirable results be obtained.


Limitations


Despite their benefits, such studies have limitations. Relatively few good and well-characterised PET radioligands have been developed compared with the potential targets of interest in drug development, with very few outside the CNS. Owing to the demanding properties of a successful radioligand, the development of new ligands is time- consuming and risky. Ligand development is therefore not generally practical during clinical development.


Even when radioligands do exist, the level of occupancy required for efficacy is often not well understood. Although the precision of occupancy measurements can be excellent for modest occupancy, PET occupancy studies are not good at differentiating small but potentially relevant variations in occupancy for very low or very high levels of occupancy.


Interpretation of PET occupancy results can be complex. Radioligands can bind to multiple pharmacologically-relevant sites, such as different receptors or receptors in different conformations. Radioligands with a different pharmacology from the investigational drug may differentially bind to these targets.


Agonism can alter the affinity of the radioligand for the target sites, thereby altering the PET signal. For example, decreases in the D2 signal following amphetamine challenge are observed with benzamide radioligands such as [11C]raclopride. On the other hand, no change or even an increase in signal is observed with some nonbenzamide radioligands such as [11C]NMSP. This has led to the validity of the receptor occupancy model for such systems being questioned.8 Consequently, a thorough understanding of the pharmacology of the radioligand and investigational drug is required for accurate interpretation of observed changes.


Practical limitations also need to be considered. The temporal resolution of occupancy changes is limited as the calculation of the specific binding signal from the PET data normally requires the assumption that occupancy levels do not significantly alter during the 60–90-minute PET scan. The number of PET scans that can be performed on a single subject are restricted by tolerability and ethical considerations, such as total radioactivity exposure. Consequently, although multiple scans might be desirable to measure occupancy at multiple time-points or for multiple doses, in practice compromises need to be made on what would ideally be measured.


DRUG DEVELOPMENT


Table 2: A Non-exhaustive List of Pharmacodynamic Positron Emission Tomography Tracers


Functional Measurement Glucose metabolism Oxygen metabolism


Other substrate metabolism Tissue perfusion Blood volume Proliferation Hypoxia


Protein synthesis Inflammation


Dopamine synthesis Cell death/apoptosis


Radiotracer(s)


[18F]fluorodeoxyglucose [15O]oxygen [11C]acetate


[15O]water, [15O]butanol, [13N]ammonia [15O/11C]carbon monoxide [11C]thymidine, [18F]FLT [18F]fluoromisonidazole


[11C]methionine, [11C]leucine [11C]PK11195 [18F]FDOPA


[18F]annexin V


Pharmacodynamic Positron Emission Tomography Studies


Over the past three decades, numerous PET tracers have been developed for measuring a variety of specific tissue functions, with some examples detailed in Table 2. Such radiotracers can be used to examine the PD response of drugs in altering tissue function related to efficacy as well as organs that could portray dose-limiting toxicity.


As with occupancy studies, separate assessment is possible for acute and chronic responses. Relationships with upstream and downstream clinical response can be examined, with downstream functional alterations likely to be more closely related to clinical outcome and side-effects.


Unlike biodistribution and occupancy studies, PD PET studies can be used to study numerous drugs with different mechanisms of action. Together with conventional clinical outcome, drug PK measurements and other PET measurements, PD PET studies enable a more complete understanding of a drug.


Limitations


As the PET signal is less specific to pharmacological action, however, observed changes can be more complex and difficult to interpret. For example, the use of [18F]fluorodeoxyglucose in monitoring response to anticancer therapy is common, with the general hypothesis that a decreased signal shows response. Short-term increases in the PET signal can be observed,9


however, as can heterogeneous response


within tumours, both of which could be predictive of response. Certain PD PET tracers are also more prone to environmental modulation, something that is a particular problem with CNS drugs.


Finally, noting the high cost and complexity of PET studies, it should be recognised that other imaging modalities, such as magnetic resonance imaging and CT scanning, can provide similar information for some functional measurements, such as blood flow.


Summary


In this article, a critical review of the logistics, benefits and risks of PET scanning in drug development has been conducted. With the high cost and complexity of PET scanning, it could be incorrectly interpreted that such approaches do not have a role in clinical drug development. With careful choice of the numerous options and consideration of the logistics, however, PET scanning can be of considerable utility, providing information that cannot be obtained with alternative methods.


41


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68