Molecular imaging with SPECT as a tool for drug development☆
Introduction
Every year thousands of new chemical entities with therapeutic potential enter preclinical research. From these, about 5–10% progress beyond the earliest stage of development and only one in five that enters clinical trials obtains a marketing approval [1]. The length of the whole process, from the discovery of the compound to its regulatory approval by the US Food and Drug Administration (FDA) takes an average of 12 to 15 years and the total expected costs are estimated at US$802 million [1]. The low predictability of toxicity and efficacy based on traditional preclinical studies are the leading causes of the high failure rate of new drug candidates that occurs during clinical trials and for the prolonged timeline and associated high costs [2], [3]. The situation is rather common with the development of the new so-called molecularly targeted agents for cancer treatment, whereas the availability of validated biomarker signals that correlate with clinical endpoints could predict which new drugs will have clinical efficacy before moving to human testing [4]. Therefore, it becomes urgent the adoption of new strategies that are able to identify earlier the promising candidates to move forward clinical trials and to discard the ones that are unlikely to be successful before moving into larger trials. In order to accomplish this goal the FDA introduced in 2006, a guide on exploratory Investigational New Drug (IND) studies to accelerate the development process of new pharmaceutical agents and to increase the success rate of agents entering clinical trials [5]. The exploratory IND studies, also called Phase 0 studies are intended to provide clinical information for a new drug candidate in an earlier phase of drug development. These clinical trials take place early before the typical Phase I trial and involve a limited human exposure to the drug candidate and have no therapeutic intent [6]. Therefore the preclinical pharmacology and toxicology testing required before initiating a Phase 0 trial is less extensive which enables these tests to be initiated sooner compared to a traditional IND [5]. The main endpoints of clinical studies performed under the guidance of an exploratory IND trial might include selection of the lead agent from a group of compounds, drug pharmacokinetics or pharmacodynamic evaluation, drug–target binding affinity, measurement of drug effect and patient selection for subsequent studies [6].
Advances in molecular imaging technology and imaging probes have extended the application of non-invasive imaging approaches into drug discovery and development programs. Radionuclide-based molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) allow the non-invasive visualization, characterization and quantification of biological processes occurring at cellular and subcellular levels in intact living subjects [7], [8]. Such techniques have proven to be useful throughout the drug discovery and initial stages of clinical testing, and are considered as a decision-making tool in the drug development process. In early clinical development, nuclear imaging techniques can be used on validation of potential drug targets, drug pharmacokinetics and biodistribution evaluation and assessment of drug–target interaction [7], [8]. Moreover, they can provide insights into the mechanistic aspects linked to the therapeutic intervention (proof-of-principle) and on the proof-of-concept testing through the use of imaging-based biomarkers [9]. The proof-of concept is demonstrated when the drug-induced biological changes provide a clinical benefit. A considerable number of potential imaging biomarkers labeled with positron and γ-emitting radionuclides have been developed and are currently in preclinical or clinical evaluation [9], [10]. Some of them are likely to have a major impact on drug development as they provide relevant readouts of drug–target interaction and of drug efficacy in early clinical studies [11].
This article outlines the potential applications of SPECT imaging in exploratory IND studies and how this approach can facilitate and accelerate new drug approvals.
Section snippets
Basic principles of SPECT imaging
Single-photon emission computed tomography (SPECT) is a sensitive nuclear imaging technique that provides a 3D spatial distribution of single-photon emitting radionuclides within the body. The detection of γ-rays is achieved through the use of a gamma-camera, which consists of a scintillation crystal, optically coupled to an array of photomultiplier tubes, which converts the γ-rays into electric signals. Multiple 2D images, also called projections, are acquired from multiple angles around the
Applications of SPECT in exploratory IND studies
The exploratory investigational new drug (IND) studies aim to provide crucial information for a new drug candidate at an early stage of clinical drug development. These studies take place early on Phase I prior to the traditional dose escalation, safety and tolerance studies that ordinarily initiate a clinical drug development program [6]. It involves a very limited human exposure, and has no therapeutic or diagnostic intent. An exploratory IND study can provide valuable information of a
Molecular imaging biomarkers in early clinical development
In the context of drug development, imaging biomarkers have gained interest as a way to assess the efficacy, the safety and the mechanism of action of drug candidates [40]. A biomarker is by definition any characteristic (anatomical, physiological, biochemical or molecular) that can be objectively measured and evaluated as an indicator of a normal or pathological process and to evaluate pharmacological response to therapeutic intervention [41]. By logical extension, imaging biomarkers may be
Future challenges
Molecular imaging has become in recent years an attractive tool in drug development with applications ranging from preclinical research to early clinical trials. As discussed above, SPECT imaging provides a relatively simple and minimally invasive approach to obtain measurable indications of the pharmacological properties and therapeutic efficacy of novel drugs in early clinical drug development using only minimal amounts of the substances to be tested. Therefore, the introduction of imaging
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This review is part of the Advanced Drug Delivery Reviews theme issue on "New Strategy for Drug Development with Exploratory IND Studies: Scientific Basis and Future Directions”.