WO2021092096A1 - Dosage individualisé de traceurs radioactifs pour imagerie - Google Patents

Dosage individualisé de traceurs radioactifs pour imagerie Download PDF

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WO2021092096A1
WO2021092096A1 PCT/US2020/058984 US2020058984W WO2021092096A1 WO 2021092096 A1 WO2021092096 A1 WO 2021092096A1 US 2020058984 W US2020058984 W US 2020058984W WO 2021092096 A1 WO2021092096 A1 WO 2021092096A1
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counts
roi
packaging unit
image
tracer
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PCT/US2020/058984
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Reinhard Koenig
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Likeminds, Inc.
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Publication of WO2021092096A1 publication Critical patent/WO2021092096A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K51/0448—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil tropane or nortropane groups, e.g. cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications

Definitions

  • the present invention is in the field of medicine. More particularly, the invention relates to radiopharmaceutical imaging of dopaminergic disorders.
  • imaging agents or tracers used for patient imaging are not dosed according to body weight and other customary parameters applied to other pharmaceutical formulations.
  • body weight For example, for brain imaging, no dose adjustment of the administered amount of radioactive imaging agent is currently made in practice or in the label of radioactive imaging agents approved by regulatory authorities. This means, in effect, that when undergoing an imaging exam, all patients will receive the same amount of radioactive tracer, resulting in a pre-set dose of radioactive exposure, irrespective of age, organ function, specific activity of enzymatic systems, and/or body weight.
  • a tracer used for brain imaging will be dependent on the general circulation of the patient to be imaged, cardiac output, his or her body weight, internal distribution spaces, metabolic activity, specificity of receptor binding, and internal metabolism of the tracer and associated molecules.
  • Radioactive tracers is done in batches of a certain size and decay-time of the radioactivity. These parameters are calculated to coincide with an optimal dose of radioactivity manufactured at a radiopharmaceutical facility and then shipped and delivered to an imaging center where the patient at the time of imaging, for example, a SPECT brain imaging.
  • a dose of tracer is manufactured, shipped, and provided in a fixed volume of aqueous or other solution, and then administered intravenously.
  • the dose of administered radioactivity is calculated as a function of decay time between manufacture of the dose and time of administration.
  • a minimum dose of radioactivity is required, which is determined by the time between manufacture of the dose, not by the volume of the tracer to be administered. Therefore, all patients undergoing a SPECT or PET exam, for instance, will receive a radioactive dose of tracer that is not adjusted by body weight and other patient-specific parameters as it would be with other pharmaceutical compounds.
  • the disclosure provides a method of imaging the DAT receptors in a region of interest (ROI) in the body of a subject, comprising: administering a first packaging unit of radiolabeled tracer, the first packaging unit comprising a less than a number of counts sufficient to image the RO, and the radiolabeled tracer having a dopamine transporter specificity of greater than 1 : 2; acquiring the counts from the ROI starting at about 15 minutes after administration of the first packaging unit; administering a second packaging unit of radiolabeled tracer if the counts acquired after the administration of the first packaging unit are not sufficient to provide a complete image of the ROI, the second packaging unit comprising less than a number of counts sufficient to image the ROI, and the radiolabeled tracer having a dopamine transporter specificity of greater than 1 : 2; acquiring the counts starting at the time that the second packaging unit is administered; determining if the counts acquired are sufficient to provide a complete image of the ROI; and repeating the administration and acquiring steps if
  • the amount of administered radiolabeled tracer in the packaging unit is determined from by the pharmacokinetic profile of the patient and measured by acquired counts in the ROI.
  • the packaging units contain at a pre-determined timepoint within the decay time of the tracer with an initial dose of about 0.25 mCi to about 0.5 mCi of radiolabeled tracer.
  • the radioactive tracer is a radiolabeled tropane
  • the tropane comprises 2b -carbomethoxy- 3p-(4-iodophenyl) tropane beta- CIT); 2 -carbomethoxy-3 -(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT), TRODAT-1, or a derivative thereof.
  • the radiolabeled tracer comprises 123 I]-E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo-E-allyl) nortropane (DaT2020), [ 123 I]-2b carbomethoxy- 3 -(4-iodophenyl)tropane ([ 123 I]-beta-CIT); [ 123 I]-2b- carbomethoxy-3P-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([ 123 I]-FP-CIT); [ 123 I]- altropane; and [ 99 mTc] -TRODAT-1.
  • the ROI sought to be imaged is the brain, kidney or cardiovascular system.
  • the counts are acquired by PET, SPECT, or an external sensor.
  • more than a first and a second packaging unit of radiolabeled tracer are administered to acquire a complete image.
  • the methods further comprising comparing the complete image obtained from the patient with a corresponding image of the ROI obtained from a control subject, the patient being afflicted with a dopaminergic disorder if the number of counts, pattern, and/or density of counts acquired to provide the image of the ROI is less than the number, density and pattern of counts acquired to provide an image of the ROI from the control subject which is not afflicted with the dopaminergic disorder.
  • the patient is determined to be afflicted with idiopathic Parkinson’s disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular parkinsonism (VaP), among other rarer causes of parkinsonism), and Lewy body dementia, ADHD, clinical depression, anxiety, sleep disorders, obesity, sexual dysfunction, schizophrenia, pheochromocytoma, binge eating disorder, or diabetes.
  • PSP progressive supranuclear palsy
  • MSA multiple system atrophy
  • CBD corticobasal degeneration
  • VaP vascular parkinsonism
  • Lewy body dementia ADHD, clinical depression, anxiety, sleep disorders, obesity, sexual dysfunction, schizophrenia, pheochromocytoma, binge eating disorder, or diabetes.
  • the disclosure provides a method of dosing a patient with a radiolabeled tracer that specifically recognizes striatal DAT receptors and that has selectivity for a dopamine transporter versus a serotonin transporter of greater than 1 : 2 (dopamine : serotonin transporter) , to obtain an image of a region of interest within the body of the patient.
  • the method comprises administering a first packaging unit of radiolabeled tracer which comprises less than a number of counts sufficient to image the ROI, and which has a dopamine : serotonin transporter specificity of greater than 1 : 2.
  • Counts are acquired from the ROI starting at about 1 minute to about 5 minutes after administration of the first packaging unit. If it is determined that the counts acquired are sufficient to provide a complete image of the ROI, then no additional packaging units are administered. If it is determined that the counts acquired are not sufficient to provide complete image of the ROI, then the administration and acquiring steps are repeated until the counts acquired are sufficient to provide a complete image of the ROI.
  • kits comprising multiple packaging units of a radiolabeled tracer that has a dopamine : serotonin transporter specificity of greater than 1 : 2, each packaging unit comprising a less than a number of counts sufficient to image a region of interest in a subject’s body.
  • the kit provides one to 10 packaging units of radiolabeled tracer. In other embodiments, the kit provides 2 to 8 packaging units of radioactive tracer. In yet other embodiments, the kit provides 2 to 5 packaging units of radioactive tracer.
  • each packaging units have from about 0.25 mCi to about 0.5 mCi radiolabeled tracer.
  • the packaging units contain about 0.5 ml to about 2 ml, about 0.25 ml to 1 ml, about 0.5 ml to 0.75 ml, about 0.5 ml, or about 1 ml volume.
  • the radioactive tracer is a radiolabeled tropane
  • the tropane comprises 2b -carbom ethoxy- 3P-(4-iodophenyl) tropane beta-CIT), 2P-carbomethoxy-3 -(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), TRODAT-1, or a derivative thereof.
  • the radiolabeled tracer comprises 123 I]-E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo-E-allyl) nortropane (DaT2020), [ 123 I]-2b carbomethoxy- 3b-(4-iodophenyl)tropane ([ 123 I]-beta-CIT); [ 123 I] ⁇ -carbomethoxy- 3 -(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([ 123 I]-FP-CIT); [ 123 I]-altropane, and/or [ 99 mTc] -TROD AT - 1.
  • Altropane refers to E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo-E-allyl) nortropane
  • DaT2020 refers to E-2P-carbomethoxy-3P-(4-fluorophenyl)-N- (3-iodo-E-allyl) nortropane, or Altropane, in a solution suitable for IV injection.
  • tropane refers to DaT2020 and its derivatives.
  • imaging agent and “tracer” refer to molecules that can provide an image of a region of interest (ROI) in the body, and can be detected from outside the body.
  • radiationoactive imaging agent and “radioactive tracer” refer to molecules labeled with a radionuclide used to image an ROI.
  • dopamine transporter specificity refers to the ability of the radiolabeled tracer to bind dopamine receptors relative to its ability to bind serotonin receptors.
  • packing unit refers to a set volume and set amount of radioactive tracer/ml and is in a syringe or other containing useful for administration.
  • fractionated administration means the administration of more than one bolus amounts of an imaging agent effective to image an ROI.
  • the overall dose of, for example, 5 mCi, contained in about 5 ml of aqueous or nonaqueous vehicle suitable for IV administration is divided into single bolus of, e.g. , about 1 ml, representing a fraction of the overall dose of radioactivity.
  • the total dose of about ml represents the total dose that may be provided to a patient, but less than that dose may be enough to provide a complete image from that patient.
  • the present disclosure relates to methods of providing a radioactive tracer to a subject having an ROI to be imaged by PET, SPECT, external sensors, and the like, and to kits including multiple packaging units comprising a minimal amount of radiolabeled tracer which is less than useful or sufficient for obtaining a complete image of the ROI in the subject. Such methods are designed to reduce the overall exposure of patients to a radioactive tracer used for imaging an ROI.
  • pharmacologically active substances are administered in chosen therapeutically effective amounts which take into consideration the clinical condition of the patient being treated, the patient’s metabolism, body weight, and age, and potentially other physical factors.
  • a standard dose of radiopharmaceutical is provided to all patients, independent of patient characteristics.
  • ioflupane used to measure the activity of dopaminergic neurons, is being administered at a dose of 5 mCi to 8 mCi per patient, independent of patient age, weight, metabolic parameters and other factors. Since ioflupane is a tracer that is less specific to dopaminergic neurons than, for example, altropane, ioflupane will slowly bind to dopaminergic neurons in the brain after having passed through general circulation during which it is also captured by other receptor types, specifically serotonin receptors. Therefore, the kinetics and receptor binding properties of ioflupane are not suitable for dosing titration in the early phases after injection.
  • the packaging units of radiolabeled tracer according to the disclosure allow for an up-titration of the effective dose of tracer effective to obtain a complete image of the ROI.
  • these “minimal” packaging units also account for individual patient pharmacokinetics, and when administered, reduces detrimental side-effects and potential related medical repercussions.
  • Factors influencing patient pharmacokinetics include, but are not limited to, the existence of competitive receptors in vivo , body weight, metabolic activity, organ impairment, and receptor density and location that would sequester the tracer from the blood stream and would prevent it from reaching the dopaminergic neurons in the brain.
  • the tracer or imaging agent in the packaging unit is adhered or linked to a radionuclide that can be detected from outside of the body by various methods, and which has a dopamine transporter specificity of greater than about 1 : 2.
  • Receptor binding and ratios of selectivity can be derived according to the methods of Madras et al. (1998) SYNAPSE 29:93-104, Madras et al. (1998) SYNAPSE 29: 105-115, and Fischman et al. (1998) SYNAPSE 29: 128-141.
  • In vitro receptor binding studies (Madras et al.
  • Non-limiting exemplary imaging agents include tropanes such as 2b - carbomethoxy- 3P-(4-iodophenyl) tropane beta-CIT); 2P-carbom ethoxy-3 P-(4-iodophenyl)-N- (3-fluoropropyl) nortropane (Altropane), (FP-CIT), TRODAT-1, and derivatives thereof.
  • tropanes such as 2b - carbomethoxy- 3P-(4-iodophenyl) tropane beta-CIT); 2P-carbom ethoxy-3 P-(4-iodophenyl)-N- (3-fluoropropyl) nortropane (Altropane), (FP-CIT), TRODAT-1, and derivatives thereof.
  • Useful imaging agents are those with a high specificity for dopaminergic neurons, low capture rate by other receptors (serotonin receptors inside other tissues of the body, especially in the lung), and a fast binding to these dopaminergic neurons in the ROIs, e,g ., in the brain (in the case of tremor disorders in the substantia nigra of the putamen), are suitable for up-titration during image acquisition.
  • Useful radionuclides to be linked to the imaging agent include those whose emitted counts and thus patterns, levels, and/or intensity can be acquired by PET or SPECT. Alternatively, the pattern, level, and/or intensity of tracer binding to DAT can be determined by the data captured by the sensors and sent, e.g., to a data reader attached to a computer.
  • Useful radionuclides include, but are not limited to with 123 I, 124 I, 125 1, 99m Tc, 18 F or 117m Sn.
  • the isotope can be located at any position on pre- Altropane, or a derivative thereof, and can be directly linked or indirectly linked via a linker (see, U.S. Patent No. 8,574,545).
  • One suitable position is the free terminus of the haloallyl moiety.
  • An imaging agent labeled with 123 I, 125 1, 99m Tc, or 117m Sn emits counts that can be acquired by SPECT.
  • Imaging agents radiolabeled with 18 F, 124 I, or U C, emit counts that can be are acquired by PET.
  • Radiolabeled Altropane and its radiolabeled derivatives may be generated by the user through any known or developed radiolabeling procedure.
  • a reaction between a haloallyl Sn precursor (pre- Altropane) and a radionuclide under oxidative conditions is allowed.
  • Other standard methods of radiolabeling can be used as well.
  • Altropane in lyophilized form is useful, however, it can also be in aqueous form.
  • Non-limiting examples of useful SPECT-readable tracers for DAT detection include [ 123 I]-E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo- E-allyl) nortropane (DaT2020), [ 123 I] -2b carbomethoxy- 3 -(4-iodophenyl)tropane ([ 123 I]-beta- CIT); [ 123 I]-2P-carbomethoxy-3P-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([ 123 I]-FP- CIT); [ 123 I]-altropane; and [ 99 mTc]-TRODAT-l.
  • [ 123 I]-FP-CIT achieves stable binding 3 hours post-injection and remains stable for 3 hours, has a half-life of 13.2 hr, emits gamma rays with an energy of 159 keV, and is FDA approved.
  • a useful amount of radiolabeled tracer in the packaging unit is that amount that provides less than that need to provide a full image of the ROI, and which can be used for fractionated administration or up-titration.
  • a useful range includes about 0.25 mCi to about 8 mCi, about 0.5 mCi to about 5 mCi, about 1 mCi to about 5 mCi, or about 2 mCi to about 4 mCi.
  • the method according to the disclosure may be used for imaging any ROI.
  • any organ that has DAT receptors may be imaged, such as, but not limited to, in the brain, the caudate-putamen, nucleus accumbens and olfactory tubercle in the substantia nigra and ventral tegmental area, the pituitary, the central nervous system, specifically in the hippocampal dentate gyrus and subventricular zone, the pancreas, the kidney and vasculature nephron in the kidney, with proximal tubule epithelial cells showing the highest density.
  • a useful exemplary tracer is Altropane or DaT2020, labeled with Iodine 123, which can be commercially obtained, or radiolabeled derivatives thereof.
  • the radiolabeled imaging agent can be formulated for injection in a physiologically acceptable carrier solution e.g., such as an aqueous or non-aqueous solution.
  • a physiologically acceptable carrier solution e.g., such as an aqueous or non-aqueous solution.
  • a physiologically acceptable carrier solution e.g., such as an aqueous or non-aqueous solution.
  • a physiologically acceptable carrier solution e.g., such as an aqueous or non-aqueous solution.
  • a physiologically acceptable carrier solution e.g., such as an aqueous or non-aqueous solution.
  • the imaging method comprises administering a first packaging unit of radiolabeled tracer to the subject.
  • the first and additional packaging units each comprise a less than a number of counts sufficient to image the ROI, and each have a dopamine : serotonin transporter specificity of greater than about 1 : 2.
  • Counts are acquired from the ROI starting at about 15 minutes after administration of the first packaging unit.
  • a second is administered if the counts acquired after the administration of the first packaging unit are not sufficient to provide a complete image of the ROI.
  • Counts are acquired starting at the time that the second packaging unit is administered, and these counts are sufficient to provide a complete image of the ROI, then no additional packaging units are administered.
  • the present method is different than the methods used under existing dosing schemes, which are not individualized, and during which a total dose of 5 mCi would be administered in one 5 ml intravenous bolus of solution containing 5 mCi of radioactivity.
  • the present packaging units containing an aliquot of the overall dosage of radioactivity and an aliquot of the overall volume in solution of such dose of radioactivity, can be administered in succession through an indwelling catheter or other suitable venous access line.
  • Emitted photons in the case of SPECT, are counted at about one minute to 5 minutes after administration or once they passed general circulation and arrived at the dopaminergic neuron, from which they would then emit photons which are be picked up by the camera. If the signal after the first injection is too weak to be picked up by the camera, a second injection of the aliquot of the volume (and radioactivity) of the total dose will be administered. If insufficient counts after the second injection are acquired after an appropriate waiting time, additional injections are conducted in appropriate timely spacing until the desired count of emitted photons is achieved.
  • the number, pattern, and/or density of counts of the image acquired from the patient can also be measured and compared with the number, pattern, and/or density of counts of the image obtained from an age-matched control subject which is not afflicted with a dopaminergic disorder.
  • the patient is afflicted with a dopaminergic disorder if the counts, density, and/or pattern of counts acquired is less than that acquired from the control subject.
  • an individualized imaging procedure is developed based on the above-mentioned pharmacokinetic parameters. Then, a number of packaging units eventually satisfying the procedure (i.e., enabling the acquisition of a “complete” image) are administered one-by-one, or up-titrated, during the imaging procedure. It is possible that an individual is completely does after administration of one packaging unit if, e.g ., that individual has certain physiological characteristics, e.g. , is very small, light-weight, and elderly.
  • the dose administered is in less than 5 ml aliquots, e.g. , in 0.25 ml, 0.5 ml, 1 ml, 1.5 ml, or 2 ml titration steps or packaging units, each step provided in single syringes or other useful application containers.
  • the tracer content of the syringes or containers is manufactured in the same batch and therefore is subject to the same radioactive decay dynamics, depending on the radionuclide used.
  • the procedure is initiated by injection of one, or under certain circumstances, several smaller than 5 ml doses as estimated by the patient parameters.
  • the injection is done under SPECT, PET, or external sensor device control such that the patient is in the camera or in contact with the device during injection. Once sufficient counts are detected by the camera/device and appropriate algorithms to result in a “complete” image, additional administration of the radioactive tracer may be unnecessary for sufficient imaging quality.
  • Any remaining packaging units which ordinarily have been produced under the same batch and transported to the imaging facility in the same shipment, and thus have been exposed to the same radioactive decay, can be used for other subjects scheduled for the same exam at the same center in close timely proximity.
  • the present methodology using these packaging units are useful for many diagnostic and imaging methods that aid in differential diagnosis, leading to appropriate treatment of conditions where the functioning or dysfunctioning of DAT is a biomarker.
  • DAT a biomarker
  • dysfunctions of DAT resulting in dopaminergic disorders are known in the brain and CNS, as well as outside of the CNS, including pancreas, kidney, gastrointestinal tract, and cardiovascular system.
  • the present method can distinguish non-dopaminergic conditions, such as, but not limited to, non-parkinsonian or essential tremor and non- Alzheimer dementia, as well as multiple sclerosis, chronic kidney disease, stroke, traumatic brain injury, drug or alcohol use, hypoglycemia, lack of sleep, lack of vitamins, increased stress, magnesium and/or thiamine deficiencies, liver failure, mercury poisoning, and drug or alcohol addiction or withdrawal, from a dopaminergic disorder displaying similar clinical manifestations.
  • non-dopaminergic conditions such as, but not limited to, non-parkinsonian or essential tremor and non- Alzheimer dementia, as well as multiple sclerosis, chronic kidney disease, stroke, traumatic brain injury, drug or alcohol use, hypoglycemia, lack of sleep, lack of vitamins, increased stress, magnesium and/or thiamine deficiencies, liver failure, mercury poisoning, and drug or alcohol addiction or withdrawal, from a dopaminergic disorder displaying similar clinical manifestations.
  • Such dopaminergic disorders include, but are not limited to, parkinsonian syndromes including idiopathic Parkinson’s disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular parkinsonism (VaP), among other rarer causes of parkinsonism), and Lewy body dementia, ADHD, clinical depression, anxiety, sleep disorders, obesity, sexual dysfunction, schizophrenia, pheochromocytoma, binge eating disorder, and diabetes and other disorders resulting from DAT dysfunction outside of the CNS. [0060] These methods can also be used in clinical trials designed to evaluate the efficacy of new treatments for DAT dysfunction to stratify subjects according to disease stage. These methods are also useful for monitoring the effectiveness of treatments for and progression of DAT dysfunction over time.
  • a clinical study is conducted that assesses the diagnostic information on dopamine activity in the striatum that can be read from SPECT images using altropane, representative of a tracer with fast distribution and high receptor affinity for dopaminergic neurons in the brain.
  • the study is conducted in patients with early and late Parkinson’s Disease (PD) and in healthy volunteers (HV).
  • Subjects appropriate for each of three cohorts are selected as follows. Late PD subjects have a Modified Hoehn and Yahr score of between 3 and 5 during “ON state”. An even spread of late stage PD patients within this range are used. Early PD have a Modified Hoehn and Yahr score of between 1 and 2.5 during “ON state”. An even spread of early parkinsonism patients within this range are used.
  • the inclusion/exclusion and cohort criteria are designed to ensure that study subjects are stratified, as reliably as clinically possible, into early- or late PD patients or are healthy. Subjects > 40 years of age are included in the study, as the occurrence of PD in patients less than 40 years of age is unusual. The inability to lie supine for 1 hour excludes subjects who are unsuited for SPECT scanning procedures.
  • the drug substance or tracer, Altropane, [ 123 I]-2p-carbomethoxy-3P-(4- fluorophenyl)-N-(3-iodo-E-allyl) nortropane is made according to known methods, with no carrier added. Alternatively, the tracer is commercially available from LikeMinds.
  • the chemical mass of drug substance in a 3 mCi to 5 mCi (111 to 185 MBq) dose is not more than 16 ng.
  • the radioactive isotope of the drug substance, [ 123 I] emits a 159 keV gamma ray which is readily detected by suitable SPECT cameras. The radioisotope has a half-life of 13.2 hours.
  • the molecular formula is CisEbiFINCk.
  • the anhydrous formula weight is 425 Da.
  • the drug substance is manufactured and handled according to the applicable Good Manufacturing Practice (GMP) at a qualified production facility. Before release, each batch of investigational product is assessed by a number of quality control tests according to methods approved by the sponsor. The batch produced meets pre-specified criteria for color, clarity, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, radioactive concentration, total vial radioactivity, pH, bacterial endotoxin level, and autoclave requirements.
  • the final product is formulated as a sterile solution for intravenous injection.
  • the drug substance is provided in a formulation suitable for human IV administration. It contains excipients previously approved by the FDA for other intravenously delivered products.
  • the drug substance is provided in a clear, colorless, sterile solution in 5 single-use pre-filled syringes, each of which containing approximately 1 mCi at the timepoint of patient injection.
  • the subject packaging units are prepared from a production batch in a way that at the timepoint of administration, the volume is about 0.5 ml and contains 1 mCi of Altropane in solution.
  • Trial participants are administered Altropane in solution under the direct supervision of a nuclear medicine physician or designee.
  • a nuclear medicine physician or designee For administration of Altropane in solution, access into a large vein (e.g ., antecubital vein) is established using a suitable intravenous (IV) catheter that does not contain silicone.
  • IV intravenous
  • each study participant While being placed in the SPECT camera, with the camera in “on” mode, i.e., collecting emitted photons from the subject’s ROI (head), each study participant receives an initial single IV injection of Altropane in a solution with a total activity dose amounting to about 1 mCi. Altropane in solution is administered manually via slow IV injection, followed by a 10 mL saline flush.
  • the exact radioactive dose administered is determined by calculating the difference between the radioactivity in the syringe and delivery system immediately before and after injection. After the dose is delivered, the syringe is filled with a volume of saline equal to the administered dose volume and the syringe is recounted under the same conditions as used to determine the dose; separately, the delivery system is placed in a suitably sized plastic container and counted in the dose calibrator using the same parameters as used for the dose. Measured radioactivity values and times of measurement are documented in the source documents and recorded in the eCRF, as well as the total injected volume.

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Abstract

L'invention concerne un procédé de dosage individualisé pour l'imagerie des récepteurs DAT dans une région d'intérêt dans le corps d'un sujet à l'aide de multiples unités de conditionnement sous-optimales de traceur radiomarqué, et de trousses pour sa mise en œuvre.
PCT/US2020/058984 2019-11-06 2020-11-04 Dosage individualisé de traceurs radioactifs pour imagerie WO2021092096A1 (fr)

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US201962931394P 2019-11-06 2019-11-06
US62/931,394 2019-11-06
US202062958934P 2020-01-09 2020-01-09
US62/958,934 2020-01-09

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