Current Pharmaceutical Design - Volume 15, Issue 9, 2009

Radionuclide imaging together with other non-invasive imaging techniques have found a prominent place in the whole drug discovery and development process. The application of imaging has the potential to alter the direction of the development process. The fundamental questions to address are when in the development timeline do you use these imaging techniques and what is the current utilization of these imaging technologies? Imaging in psychopharmacology and CNS disorders, plays a critical role in drug development, because often nonclinical models do not exist (Pauwels et al.) [1]. Structures to be imaged are often small, location has to be known very precisely to estimate function disturbances and macrodosimetry is therefore more accurate. This issue focuses more on the targets outside the brain, main focus is therefore in cancer drug and cardiovascular drug development. Dosimetric and pharmacokinetic aspects are more complex and therefore discussed thoroughly. In this issue, cardiovascular drug development has been reviewed by academic network with members from Europe, North America and Japan (Ukkonen et al.) [2]. In this field there is an emerging need to understand the effects of drugs. Radiolabelled compounds offer possibility to study noninvasively cardiac perfusion, oxygen consumption, oxidative and substrate metabolism, myocardial efficiency of work, neural actions and receptors. Radiopharmaceuticals provide invaluable tool to study different routes of administration. Most cardiovascular drugs are oral and cancer drugs systemic intravenous. Inhalation provides benefits over other routes of administration, e.g. avoidance of firstpass- metabolism, and convenience for patients in administrations without repeated injections. Drug development of inhaled substances is complicated and usually development times are longer than ordinary drug development. The dosage in inhaled drugs causes many uncertainties as reviewed by Jekunen [3].

The advances of nuclear medicine imaging instrumentation and radiopharmaceutical sciences allow their involvement in the developmental processes of therapeutic drugs. New chemical entities, meant as potential drugs, need to comply with the proof- of- principle. Tomographic imaging methods as PET, SPECT and CT have been used for small animal and human studies at an early stage of drug development. Using a drug candidate in a radiolabeled form in obtaining quantitative imaging data provides opportunity for a complete morphological and functional overview of targeting properties and overall pharmacokinetics. This can be helpful in go/ no- go decision making. Microdosing, using e.g.1% of the proposed dose of the radiolabeled potential drug plays an important part in this early development and notably reduces the risk of serious adverse effects in human volunteers or patients. This paper primarily focuses on the way in which microdosing and SPECT imaging may contribute to the development of drugs. Furthermore, this paper illustrates how these techniques may help to eliminate weak drug candidates at early stage, making time and funds available for potential lead compounds. Eventually this approach facilitates and accelerates new drug approval. The present paper highlights how these techniques make drug development easier in the field of oncology and neurology.

Radiopharmaceuticals can provide unique information for drug development also in cardiovascular applications. Radiopharmaceuticals offer possibility to study noninvasively cardiac perfusion, oxygen consumption, oxidative and substrate metabolism, myocardial efficiency of work, neural actions and receptors, vascular inflammation, and molecular processes which all are relevant to understand the effects of drugs. Using these surrogate end points, hypotheses can be tested in vivo in phase I and II clinical studies before starting large-scale clinical phase III or IV trials. In addition, these approaches may allow improved selection of drug therapy for a given patient. Modern techniques such as gene therapy technology provide numerous new potential mechanisms of action and targets for drug development. Device therapies and cell therapies are also under rapid development. Molecular imaging has great potential in evaluating these new therapies and selecting the patient populations and monitoring of the effect of therapy.

Inhaled drugs have been recognized for their great potential for improved drug delivery, but so far only a fraction of their potential is benefiting clinical practice. Many new promising drug candidates are in development pipelines and some of them are approaching processes of regulatory agencies. Overall, investigation in inhalation drug development is intense. Inhalation administration route provides benefits over other routes of administration, e.g. avoidance of firstpass- metabolism, and convenience for patients in administrations without repeated injections. However, drug development of inhaled substances is complicated and usually development times are longer than ordinary drug development. Additional investigational needs in development of inhaled drugs are dealing with formulation, devices and variability of respiratory function between human subjects. Radiopharmaceuticals provide invaluable tool to explore these issues noninvasively. First, radiopharmaceuticals can be used in vitro for proof of concept studies. Second, they are used to resolve depository issues, as well as to give timeframe for clearance of substances in target organs. Third, radiopharmaceuticals' new potential use is focused on extending non-invasive imaging technique towards true pharmacokinetic modelling via calculations of target organ follow-up and exposure. Exposure estimates of a particular drug candidate make safety evaluation feasible early in the drug development. Safety issues can be resolved by investigating exposures of target organs, and depository and absorption issues in airways.

In the last decade radiotracers have been gradually growing in importance as aids for the development of new drugs. This development has been most pronounced for Psychiatric and Neurologic drugs [1, 2], but has more recently been adapted to the development of drugs against cancer. In this mini-review, we describe how advances in molecular imaging of cancer are likely to lead to advances in development and improved application of anti-cancer drugs [3]. We will focus on 4 aspects of use of radiotracers: 1) for treatment response assessment; 2) for the study of kinetics and pharmacology of novel drugs, including bioavailability and local tumor concentration; 3) the identification of the biologic target at the cellular level; 4) the combination of nanocarriers and radioisotopes to improve biodistribution.

Oncology remains an increasingly important focus of therapeutic development yet there remain many scientific and operational bottlenecks to deliver optimum treatments efficiently. Radiopharmaceuticals constitute a group of methodologies able to support the many stages of drug development. Methods such as [18F]-FDG-PET continue to have a role, evaluating early metabolic response to treatment and supporting more conventional assessments of disease response. Improvements over such tracers (for example, use of [18F]-FLT) in certain settings can also widen the impact radiotracers have on clinical development. New categories of tracers able to provide molecular insight into therapeutic intervention are likely grow and aim to remove the ambiguity of how effective a new drug is. It is likely that newer tracers able to define processes such as angiogenesis and apoptosis will supplement other methods in supporting early development decisionmaking and de-risking expensive, late-stage programs. Labeled drugs themselves also offer the ability to study localised pharmacokinetics in vivo and study issues such as therapeutic combinations. Owing to the significant cost, resource and time investment in developing novel tracers, new opportunities need to be closely matched with emerging drug development needs.

Determination of individual pharmacokinetics in patients undergoing radiopharmaceutical therapy is essential to define critical normal organ dosimetry. Review of a 20 year single institution experience demonstrates practical methodology for routinely characterising pharmacokinetics in each patient and calculating safe, effective therapeutic activities predicated upon prescribed radiation absorbed doses to the critical organs. In particular the results achieved in over 100 unselected consecutive clinic patients treated with 131I-rituximab radioimmunotherapy for relapsed/refractory non- Hodgkins lymphoma have matched the ORR of 75% and CR 50% achieved in formal phase II clinical trial. The low level of myelotoxicity was attributed to prospective dosimetry in each patient and prescribed dose of 0.75 Gy to whole body. Radiopeptide therapy of progressive neuroendocrine tumours with 177Lu-octreotate, illustrates application of practical dosimetry using retrospective quantitative imaging to define individual pharmacokinetics. Further challenges of multimodality combination therapy using radionuclide cocktails, chemotherapy and antivascular therapy, which will perturb pharmacokinetics, will require creative dosimetric methodology for continued safe, effective clinical practice of therapeutic nuclear oncology.

Imaging of glucose metabolism has resulted in significant improvements in staging and follow-up in oncology. 18F-FDG PET has become a routine clinical test for most solid tumours. Several radionuclide-labeled derivatives of deoxyglucose that have shown that glucose metabolic imaging may be a useful tool for improving tumour staging, restaging, and monitoring of tumour response to therapy.

Physiology based pharmacokinetic (PBPK) modeling and simulation is a useful method for prediction of biodistribution of both macromolecules and small molecules. It can enhance our understanding of the underlying mechanisms of biodistribution and hence may help in rational design of macromolecules used as diagnostic and therapeutic agents. In this review we discuss PBPK modeling and simulation of a radiolabelled Monoclonal Antibody (111In-DOTA-hAFP31 IgG) (“MAB”) in mice without tumor and in a human with tumor. This study is part of Xemet Co.'s effort to develop a more accurate and reliable PBPK model and simulation platform, which is applicable both for small molecules and macromolecules. The simulated results were fitted to experimental time series data by varying parameters which were not fixed a priori. It was demonstrated that the PBPK model describes the main features of the pharmacokinetics of the studied systems. It was also shown that simulation can be used for evaluating the parameters of the system and scaling up the pharmacokinetics of MAB from mice to man. We identified several areas of improvement and further development needed to improve the accuracy of PBPK simulation for MAB and other macromolecules. It was concluded that the transvascular permeabilities are the most important parameters and more research is needed to enable prediction of permeabilities from molecular characteristics of macromolecules. It would also be necessary to understand better and describe with a more detailed model the microstructure of the tumor and to measure or predict the antigen concentration in tumor. Non-specific, non-saturable binding in other organs/tissues should be understood better and the kinetic constants of the binding should be measured experimentally. Although the metabolism and clearance were neglected in this study they need to be included in more detailed studies. Also the intracellular trafficking of macromolecules, which was not included in this study, shall be included in the more accurate models.

Neuropathic pain affects 26 million patients worldwide resulting in a worldwide healthcare cost over $ 3 billion per year. Despite the availability of an impressive arsenal of powerful drugs for the effective management of pain, there remains a great medical need for new medicines to treat pain. While little is known about the proteins that detect noxious stimuli (especially those of a physical nature), vanilloid receptor, an excitatory ion channel expressed by nociceptors, has been identified as molecular target for the development of recent therapies to treat pain. Initially, the focus was on the development of TRPV1 agonists e.g. capsaicin and resiniferatoxin (RTX) as analgesic agents through the desensitization/ denervation approach. While various formulations of capsaicin are either marketed or are currently under development, this approach is often hindered by the pain and discomfort experienced on initial treatment. Thus, TRPV1 antagonists are being evaluated as promising drug candidates to inhibit the transmission of nociceptive signals from the periphery to the CNS and to block other pathological states associated with this receptor. Since the discovery of capsazepine as the first TRPV1 antagonist, multiple classes of antagonists has been reported that can be broadly classified as urea/amide-based and non-urea/non-amide-based agents. However, depending on their chemical structures all these agents can be grouped as benzenesulfonamides, cinnamides, ureas, thio-ureas, amides, benzimidazoles, and piperazine carboxamides, N-aryl-cinnamides etc. The present review will focus on all these antagonists as an emerging class of novel, analgesic, antiinflammatory agents that have been reported in the literature over the last several years and the status of the developmental candidates in various stages of clinical trials.

Although remarkable therapeutic advances in the treatment of cardiometabolic disorders have been made with current therapeutic options, cardiovascular disease (CVD) is still a leading cause of mortality and morbidity in the Western world. Therefore, to develop a novel therapeutic strategy is needed for the prevention of cardiovascular disease (CVD) in high-risk patients for atherosclerosis. Recently, we, along with others, have shown that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, exerts anti-oxidative and anti-inflammatory properties in vascular wall cells, leukocytes and platelets. In addition, PEDF not only suppresses neointimal hyperplasia after balloon angioplasty, but also blocks occlusive thrombus formation in a rat arterial thrombosis model. These observations suggest that substitution of PEDF may be a novel therapeutic strategy for atherosclerosis. This article summarizes the pathophysiological role of PEDF in atherosclerosis and its potential therapeutic implication in this devastating disorder. We also discuss here the kinetics and regulation of PEDF in cardiometabolic disorders in humans.