Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 6S rejected. One goal in drug development research should be to develop innovative methodology for fully rejecting targets. In order to improve target validation and rejection, a greater focus is required on the Target Validation Space (i.e., preclinical research through to FDA/Investigative New Drug application (IND) Phases I through III. A target can be thought of as being a molecular structure/site in the brain or a particular electrical current. Research Domain Criteria (RDoC) is a novel way that the National Institute for Mental Health (NIMH) has devised whereby a target can be exactly as described above and a site is targeted that may underlie a symptom without necessarily being associated with a disease. RDoC avoids using the fourth or fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, DSM 5) and instead focuses on particular systems underlying specific behaviors. These systems include Negative Valence Systems, positive valence systems, cognitive systems, social systems, arousal, and modulatory systems. 1 A new program (Fast fail trials) has also been designed to begin targeting such systems, especially examining new or repurposed compounds for their potential as psychiatric medications. This mechanism will also investigate whether the compound engaged specific targets in the brain by altering brain signaling or a specific neurotransmitter. Importantly, no one group could possibly investigate each of these areas and so academia and industry must come together. These topics were covered in The International Society for CNS Clinical Trials and Methodology (ISCTM) Autumn 2013 meeting on the topic of translational and early development strategies and tools led by Drs. Potter and Feltner. This report comprises a review of those proceedings with a concluding summary to advance future clinical trials. THE IMPORTANCE OF TRANSLATIONAL PHARMACOLOGY Translational pharmacology is essential to ensure that the drug candidate is capable of testing the drug efficacy and hypothesis. 2 The goal, thereafter, is that the early preclinical pharmacological data will predict clinical efficacy. Numerous important aspects to measuring translational pharmacology should be considered, including plasma or cerebrospinal fluid levels, ex-vivo binding, micro-positron emission tomography (PET), and dose response curves. Table 1 provides a fictitious example of such considerations for a dopamine D 1 receptor agonist. Ultimately, it is important for researchers to examine the pharmacology translation alongside the efficacy translation. While conducting translational pharmacological research, there are numerous caveats and complexities that must be taken into account. For example, preclinical data on exposure and occupancy may be inconsistent so there would be less certainty in the translation to human data. Inverted u- shape dose response curves also exist, in both animals and humans, that require careful reviews of the data. Another complexity in translational pharmacology is off-target effects impacting biomarker and pharmacodynamic responses. Another important and often overlooked complication is whether there are differences between chronic or acute effects, and whether the drug would be used as an adjunctive treatment in already approved medications. Thus, drug interactions should be assessed when translating pharmacological effects. One other issue that often adds complexity is that the occupancy/exposure required in an animal model may differ from that required in human diseases. In fact, differences may also be seen between healthy humans and those suffering from disease. Ultimately, quantitative translation attempts to set a minimum exposure level to test the hypothesis and hence search for consistency in biomarker data, especially in novel targets. If this is not possible and current methodologies are the only path forward, then novel target development or rejection might be limited. GO/NO-GO DECISION-MAKING AFTER RIGOROUS EARLY PHASE DRUG EVALUATION Such translational pharmacology can be pivotal in drug development. For instance, determining whether similar occupancy levels occur between preclinical and clinical TABLE 1. Fictitious example of the translational pharmacology of a dopamine D 1 receptor agonist D OPAMINE D 1 RECEPTOR AGONIST P RECLINICAL QUANTIFICATION ASSOCIATED WITH "EFFICACY" CLINICAL DECISION CRITERION COMMENT Occupancy/exposure Brain ECF drug level, >200 ng/ml CSF drug level > 200 ng/ml (LL 9 0% CI) Not closely linked to target P D Marker Increased FDG-PET signal in PFC in NHP and 2DG in rat at > 200 ng/ml Increased FDG-PET signal in human PFC at > 350 ng/ml Provides regional localization; not closely linked to target 2DG: 2=deoxy-D-glucose; CI: confidence interval; CSF: cerebrospinal fluid; ECF: extracellular fluid; FDG: FluoroDeocyGlucose; NHP: nonhuman primates; PET: positron emission tomography; PFC: prefrontal cortex

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