* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download The Role of Neuroimaging in Clinical Trials and Drug Discovery In
5-HT2C receptor agonist wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Discovery and development of beta-blockers wikipedia , lookup
Atypical antipsychotic wikipedia , lookup
Discovery and development of antiandrogens wikipedia , lookup
NMDA receptor wikipedia , lookup
Pharmacognosy wikipedia , lookup
Toxicodynamics wikipedia , lookup
5-HT3 antagonist wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
Prescription costs wikipedia , lookup
Nicotinic agonist wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Drug interaction wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Theralizumab wikipedia , lookup
Drug discovery wikipedia , lookup
Drug design wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Psychopharmacology wikipedia , lookup
The Role of Neuroimaging in Clinical Trials and Drug Discovery In Psychiatry Joseph C. Masdeu, MD, PhD Section on Integrative Neuroimaging National Institutes of Health Neuroimaging in Drug Discovery and Development Preclinical models Early clinical experiments to demonstrate 'proof of biology' Linking target engagement (TE) to drug-induced biological changes expected to give clinical benefit Clinical trials to demonstrate proof of concept (PoC), Engaging a particular target is linked to a meaningful change in a clinical end point thus demonstrating a new avenue to treat a condition in patients The Glycine Transporter 1 and Schizophrenia In schizophrenia NMDA function is impaired Lisman JE et al. Trends Neurosci. 2008;31:234 GlyT-1 regulates glycine levels at NMDA sites Glycine is an essential coagonist of NMDA receptors GlyT-1 inhibitors enhance NMDA function (preclinical studies) Selective GlyT-1 inhibitors are being studied as drug candidates for schizophrenia Catafau A et al. Neuroreceptor Meeting. Pittsburgh 2008 [11C]GSK931145: A New PET Ligand for Glycine Transporter 1 Transporter characteristics Autoradiography Physiology Pharmacology [11C]GSK931145: A New PET Ligand for Glycine Transporter 1 Pig Primate Human [11C]GSK931145 distribution in a healthy volunteer [11C]GSK931145: A New PET Ligand for Glycine Transporter 1 This new GlyT-1 PET ligand is being applied to: Understand the role of GlyT-1 in Neuropsychiatric disorders Drug development pharmacokinetics (PK) receptor occupancy (RO) pharmacodynamics (PD) dose estimations New Drug Characteristics Properties of Drug Candidate Determined by Neuroimaging Whether it crosses the blood–brain barrier And, thus, it is delivered to the target compartment (ie the brain) Whether it engages the appropriate target Receptor Transporter Enzyme in a dose/exposure-related manner Uses of PET in Drug Development Two main approaches Radiolabel the new drug Estimate target occupancy By the new drug Drug Candidate Biodistribution Usual Radioisotopes: and Kinetics PET: [11C], [18F] SPECT: [123I], [99mTc] Ideally, a new lead drug candidate should be isotopically radiolabeled with a PET or SPECT radioisotope To determine brain distribution of the compound Some of its washout characteristics Whether it is a substrate for BBB pumps More likely to induce multidrug resistance Also helpful in animal studies Limitations to Radiolabeling Candidate Drugs Primary quantitative radiotracers label only a very small number of potential drugs Brain exposure for compounds that cross the BBB slowly may be underestimated Given the short acquisition times possible with these isotopes 90 min 11C 8 h for 18F Higher brain concentrations after chronic dosing True target engagement may be overestimated Total regional brain activity is recorded, not distinguishing between binding to the test drug brain-penetrated radiolabeled metabolites of the test drug free tracer tracer nonspecific binding Instead of Radiolabeling Candidate Drug: Label Drug Target Use existing PET/SPECT tracers E.g., to the serotonin transporter to determine the target occupancy of the new drug in displacement studies More active drug Less labeled target available Serotonin Trasporter Occupancy After Rx with Paroxetine Studied with 123IADAM SPECT Decrease in midbrain uptake (71% serotonin transporter occupancy) Baseline After 6-week paroxetine 20 mg/day Catafau AM et al. Psychopharmacology 2006;189:145 PET versus SPECT for the Study of D2 Receptor Occupancy Comparing: [123I]IBZM SPECT [11C]Raclopride PET In the same subjects Occupancy values measured by SPECT were lower than those measured with PET 12.4% (occipital cortex as reference region) 13.8% (cerebellum as reference region) But the correlation between D2 occupancy using either method approximates 1.0 Catafau A et al. Neuroimage 2009, Epub ahead of print PET: Better Anatomical Definition than SPECT (D2 Receptor Occupancy Study) Functional MRI (fMRI) Arterial spin labeling (ASL) To study brain systems responses to external stimuli the modification of these responses by drug treatment In normal healthy volunteers In patients Complement neuroreceptor imaging by revealing the neurocircuitry involved in behavior and responses Fearful Left Right fMRI as Pre-Biomarker The SSRI antidepressant citalopram reduced amygdala activation in response to fearful faces in normal volunteers The amygdala response to fearful stimuli Happy Left Right could develop into a prebiomarker for antidepressant effects Harmer CJ et al. Biol Psychiatry 2006;59:816 Role of MRI in Drug Distribution Proton (1H) Spectroscopy (MRS) Assessment of glutamate and GABA amino acids Psychotropic drugs with GABAergic or glutamatergic mechanisms of action eg acamprosate, for the Rx of alcohol dependence 7Li-MRS has been used to measure lithium concentrations in patients' brains and to relate it to plasma concentrations (Plenge et al, 1994) fluphenazine and trifluoperazine (Durst et al, 1990) And antidepressants such as fluoxetine (Karson et al, 1993) Also contain a fluorine atom 19F-MRS has been used to determine concentrations of fluorinated antipsychotics perphenazine, risperidone, most of the butyrophenone antipsychotics, the SSRIs fluvoxamine and paroxetine several benzodiazepines and the benzodiazepine antagonist flumazenil Effect of Cytidine on Bipolar Depression and on Brain Glutamate Levels Region Studied MR spectrum Anterior Cingulate Gyrus Yoon SJ et al. Neuropsychopharmacology 2009 [Epub ahead of print] Scores on the Hamilton Depression Rating Score Cytidine Effect Linked to Glutamate Studied with MR spectroscopy Yoon SJ et al. Neuropsychopharmacology 2009 [Epub ahead of print] Biomarker Characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacological responses to a therapeutic intervention Frank R, Hargreaves R. Nat Rev Drug Discov 2003;2: 566 Types of Biomarkers Type 0 Tracks the natural course of the disease Type 1 Examines the effects of intervention along with the known mechanism of action of the drug But without strict relationship to clinical outcome Type 2 Change in the biomarker is predictive of clinical outcome At present, most imaging methods in psychiatry do not meet the biomarker status ‘Emerging’ Biomarker or ‘Pre-biomarker’ With dopamine D2 receptor PET imaging A link was found between Dopamine D2 receptor occupancy efficacy to treat delusions, hallucinations Useful to fortify Proof of Concept for D2 DA antagonists establish a dose range to test for new, pure D2 antagonists Dopamine D2 Receptor Binding Measured with [11C]raclopride Most widely used [11C]FLB 457 Better for cortical D2 But still a [11C] compound [18F]fallypride Better for cortex, [18F] But scanning time about 4 hours D2 binding in a healthy control [11C]FLB 457 PET Takahashi H et al. Biol Psychiatry 2006;59:919 Dopamine D2 Receptor Binding in Schizophrenia Decreased D2 receptor binding in untreated schizophrenia Thalamus Dorsomedial nucleus Striatum Anterior cingulate Amygdala Temporal cortex Patients < Controls Buchsbaum MS et al. Schizophr Res 2006;85:232 ACNP 2008, Phoenix Az Measured with [18F]fluoro-DOPA PET dopamine causes down-regulation of the D2 receptors stimulation of the D2 receptors Hallucinations Treated by D2 antagonists 18FDOPA Striatal dopamine (DA) production is increased in schizophrenia striatal Ki values Reduced D2 Receptor Binding: Greater Receptor Occupancy by Endogenous DA Controls Patients Meyer-Lindenberg A et al. Nat Neurosci 2002;5:267 DA D2 Receptor Antagonists in Schizophrenia Drug: Haloperidol D2 binding studied with [11C]raclopride Effective: <80% occupancy >80% occupancy: parkinsonism or akathisia Kapur S et al. Am J Psychiatry 2000;157: 514 PET* to Assess Drug Behavior Straightforward to assess: Neutral orthosteric site antagonists Haloperidol Considerable challenges in the assessment of target engagement (TE) and linking TE to efficacy for: Agonists Partial agonists Aripiprazole Inverse agonists Allosteric modulators Many new therapeutic approaches to psychiatric disorders use positive allosteric modulators As a means to fine-tune the primary excitatory (Glu) and inhibitory (GABA) systems *In combination with structural MRI Partial Agonists: Occupancy Studies of the Antipsychotic Aripiprazole Conventional wisdom: within a 'therapeutic window' of 65–80% striatal D2 receptor occupancy D2 DA antagonists have antipsychotic efficacy with minimal EPS side effects But for aripiprazole, occupancies closer to 90 or 95% were needed for the therapeutic range of the drug Because the likely mechanism of action of aripiprazole is partial agonist at D2 receptors The original 'therapeutic window' of 65–80% receptor occupancy is valid for D2 DA antagonists only Antidepressants and dosing SSRIs have been shown to occupy 80% or more of the serotonin transporter (SERT) at clinically used doses Within this class of drugs, this seems to be independent of the specific SSRI Meyer JH, et al. Am J Psychiatry 2001;158:1843 Antidepressant Dosing and PET: The Clomipramine Paradox The tricyclic antidepressant (TCA) clomipramine occupies 80% of the SERT at doses as low as 10 mg at a plasma concentration of 1.42 ng/ml Therapeutic plasma concentrations range 175–450 ng/ml* Yet, clinically used doses are 50–150 mg per day Is blockade of the SERT and the norepinephrine transporter (NET) the therapeutic principle of clomipramine (and of the TCAs in general)? Or do TCAs behave completely different from SSRIs, due to their broad pharmacological actions at many different molecular targets? How valid are the studies upon which therapeutic doses and plasma concentrations have been determined for clinical use of the TCAs over decades? *Baumann P et al. Pharmacopsychiatry 2004;37:243 Dosing and PET A radiotracer/pre-biomarker that has been demonstrated to predict the biological effects of a certain class of compounds might lose its validity for a drug with a slight modification of its mechanism of action even if it binds to the same target molecule Imaging and Dose Finding for Clinical Trials: Rejecting New Drugs If a dose that demonstrated adequate target engagement in humans With a high degree of confidence does not have efficacy in the clinical trial Proof of concept can be rejected, and a drug target can be abandoned more quickly Rejecting a Disease Mechanism: Role of PET Aprepitant blocked the neurokinin 1 receptor Visualized with [18F]SPA-RQ PET But did not improve depression No better than placebo on the Hamilton Depression Scale Aprepitant Rx Baseline After 160mg for 40 days r Summary Conclusions Neuroimaging in Drug Development* Justification/rationale for a specific neurotransmitter receptor system as a target for therapeutic intervention E.g., dopamine, serotonin, etc Radiolabeling the potential therapeutic compound of interest to examine biodistribution and BBB penetration Rational therapeutic dosing to test efficacy efficiently in the target patient population Mechanism of pharmacological action how does the efficacious action might occur during therapeutic doses in the target patient populations *Especially as pertains to neurotransmitter and neuroreceptor imaging Thank you! Thank you! Imaging to Determine Level of Target Engagement (TE) With isotopically labeled drug candidates to estimate total brain exposure generally using either C-11 or F-18 tracers Functional studies such as measurement of test drug effects on regional cerebral blood flow (PET/SPECT or MRI) A direct measure of TE employing a PET radioligand that can be used for measuring occupancy E.g., DA D2/D3 receptor occupancy studies with [11C]raclopride. Imaging to Determine Level of Target Engagement (TE) It is challenging to determine what level of TE is needed for a novel mechanism for a class of compounds It is typically guided by efficacy studies in appropriate preclinical models Target Identification and Therapeutic Rationale Example: Hyperdopaminergic state associated with the positive symptoms of schizophrenia Studies of presynaptic DA neuron function measuring dopa decarboxylase with [18F]fluorodopa Studies demonstrating elevations in amphetamine-induced intrasynaptic DA release DA occupancy of D2/3 receptors by endogenous DA Studies showing elevation of D2 receptor density or binding potential Serotonin Trasporter Occupancy After Rx with Paroxetine Relationship between Paroxetine plasma concentrations Serotonin transporter occupancy (%SERTocc) Measured by means of 123IADAM SPECT Paroxetine plasma levels (ng/mL) Catafau AM et al. Psychopharmacology 2006;189:145 Dopamine antagonists (antipsychotics) It has been known for more than 30 years that these compounds exert their effects on the positive symptoms of schizophrenia by antagonizing DA D2 receptors (Seeman et al, 1976). It was later discovered with PET that clinically effective doses of typical neuroleptics occupy D2-like DA receptors in the human striatum in the range between 65 and 90% (Farde et al, 1992). The suggestion of a 'therapeutic window' between 60 and 80% striatal D2 RO for sufficient treatment response and a 'ceiling' of around 80% occupancy, above which extrapyramidal side effects (EPS) are likely, was later confirmed by several other researchers (eg Kapur et al, 2000). Although clozapine and quetiapine seem to be exceptions, this rule also applies for most of the secondgeneration, 'atypical' antipsychotics (Nyberg et al, 1999). When their doses are raised above a certain threshold, striatal (and potentially extrastriatal) D2 DA occupancy increases to levels that are associated with a higher incidence of EPS. As described above the relationship between doses of antipsychotic drugs and their (striatal) D2-like DA RO has almost approached the status of a biomarker, Dopamine antagonists (antipsychotics) But long-term functional outcome in schizophrenia is determined by improvement in cognitive function rather than control of positive symptoms (Bowie et al, 2006) And the available antipsychotics have limited activity against cognitive symptoms (Keefe et al, 2007) Thus, D2/D3 receptor occupancy is an incomplete marker of disease control or progression Bowie CR et al. Am J Psychiatry 2006;163:425 Keefe RD et al. Arch Gen Psychiatry 2007;64:633 Target Identification and Therapeutic Rationale Example: Hypodopaminergic state associated with the abuse of cocaine, alcohol, ecstasy… Furthermore, other evidences from studies in, as well as methamphetamine and ecstasy users, have demonstrated reductions of DA and some serotonin chemical markers supporting a concept of reduced DA function. ** Single vs Multiple Dosing of the Candidate Drug In many cases single-dose studies very accurately predict receptor occupancies achieved with multiple dosing But this might not be the situation for certain drugs E.g., ziprasidone Single-dose occupancy studies should be supplemented by subchronic studies to avoid an incorrect dose selection for large efficacy trials Single vs Multiple Dosing of Ziprasidone For occupancy studies, ziprasidone was given to healthy volunteers in single oral doses of 40-60 mg Causing a striatal D2 occupancy of 67%-85% It was concluded from these studies that effective antipsychotic ziprasidone doses should be around 40 mg But phase II clinical efficacy studies demonstrated 40 mg to be not better than placebo Ziprasidone has potent antipsychotic efficacy at 120–160 mg PET studies in patients after subchronic treatment demonstrated that the striatal D2 occupancy was markedly lower than was predicted by the early single-dose studies Single vs Multiple Dosing of Ziprasidone Vernaleken I et al. J Clin Psychopharmacol 2008;28:608 Striatal vs Extrastriatal brain Occupancy The selection of the correct brain region for determination of receptor occupancy Is an increasingly crucial issue Conventional belief of a 'therapeutic window' in the range of 60–80% striatal D2 occupancy is true for most antipsychotics But, low-affinity D2 antagonists such as clozapine or quetiapine occupy striatal D2 receptors (<50%) to a lesser extent than cortical D2 receptors (>50%) (Gründer et al, 2006; Kessler et al, 2006). A likely basis for their beneficial extrapyramidal side effect profile Mechanism of Action of Candidate Therapeutic Drugs PET imaging can provide actual empirical evidence for a drug candidate's effect or potential effect E.g., potential use of DA transporter (DAT) inhibitors in the treatment of stimulant abuse In nonhuman primates, the preadministration of the DAT inhibitor, GBR12909, blocked the amphetamine-induced DA release substantially Before the amphetamine challenge, there was an increase of basal intrasynaptic DA, which could be useful in reducing, for example, cocaine craving