Radioactive Drug Research Committee Research Articles

125. Dynamic PET facilitated Pharmacokinetic Modeling and High-dose Rifampin Regimens for Staphylococcus aureus Orthopedic Implant Associated Infections: Bench to Bedside

125. Dynamic PET facilitated Pharmacokinetic Modeling and High-dose Rifampin Regimens for <i>Staphylococcus aureus</i> Orthopedic Implant Associated Infections: Bench to Bedside

191. High-Dose Rifampin-containing Regimens for the Treatment of TB Meningitis

191. High-Dose Rifampin-containing Regimens for the Treatment of TB Meningitis

Abstract No. 137 Molecular imaging of infection: [11C]-trimethoprim imaging of biopsy-proven discitis-osteomyelitis

White blood cell scans and [18F]-FDG PET/CT studies provide functional imaging data on leukocyte localization and glucose transport within tissue but are lacking in specificity for infection. Thus, interventional radiologists are frequently consulted for biopsy or aspiration to obtain microbial cultures that provide a definitive diagnosis of infection and guide treatment selection. Carbon-11 trimethoprim ([11C]-TMP) is mechanistically more specific for bacterial infection and can be imaged by PET/CT. A protocol to investigate the human biodistribution of [11C]-TMP was approved by the University of Pennsylvania Institutional Review Board and Radioactive Drug Research Committee (NCT03424525). A patient with clinically suspected discitis-osteomyelitis, who was scheduled for upcoming L4-L5 facet biopsy, was enrolled. [11C]-TMP was injected in this patient and PET/CT images were obtained, both prior to biopsy and after 7 weeks of antibiotic therapy. Left L4-L5 facet aspiration was performed with an 18G 3.5cm spinal needle. Osseous biopsy was obtained with a 11G introducer and 13G bone biopsy system. The [11C]-TMP PET/CT images obtained at the start of therapy demonstrate asymmetric increased tracer uptake in the left L4-L5 facet and above background tracer uptake in the adjacent paraspinal musculature. After 7 weeks of IV cefazolin therapy, this signal is no longer appreciable on both dynamic and 30- to 60-minute summed images. Osseous and soft-tissue regions of geographic tracer uptake correspond with areas of T1 prolongation, T2 prolongation, and contrast enhancement by MRI, compatible with discitis-osteomyelitis with surrounding inflammation. Interventional radiology aspiration yielded a culture of methicillin sensitive Staphylococcus aureus. Bone biopsy confirmed reactive osseous findings compatible with osteomyelitis. Here we present a case of an investigational PET radiotracer [11C]-TMP, which suggests the ability to functionally and specifically image a bacterial infection in a human patient. Further investigations are ongoing, which will evaluate the potential of this technology to inform the interventional management of infection.

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC)

BackgroundIn the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing.ResultsThe University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees.ConclusionsThe data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.

Radiopharmaceuticals for Drug Development: United States Regulatory Perspective

Imaging with radiopharmaceuticals is playing an increasingly important role in the development of new drugs. At nearly every step of the process imaging may be used to assess the status of the candidate drugs and assist in determining the lead molecules for further evaluation. Incorporating imaging studies into the paradigm may ameliorate the temporal and economic cost of drug development. Since 1975 radiopharmaceuticals have been regulated as drugs and all human studies must be carried out under an investigational new drug (IND) or radioactive drug research committee (RDRC) protocol. The FDA released the exploratory IND guidance in 2006 to highlight the flexibility in the IND process while trying to stimulate new drug entry into the approval pipeline. The exploratory IND also provides a lower threshold for radiopharmaceutical and candidate drug first in human studies, using the microdosing concept, that may not be conducted under an RDRC protocol. The RDRC mechanism permits the basic research studies with limited dose and numbers of subjects. The RDRC regulations are 30 years old and the full IND process remains burdensome for radiopharmaceutical development. Therefore, it is essential that the regulatory framework permit the approval of radiopharmaceuticals for use in humans that is commensurate with the safety and applications of the probes. Beyond diagnosing and staging disease, monitoring progression or therapeutic intervention, imaging is playing an increasingly important role in the drug discovery and development process. Nuclear imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), with radiolabeled molecular entities, radiopharmaceuticals, permits the visualization of the distribution of potential drugs as well as interrogating their effect on disease, organ systems and the whole body. Imaging probes may be applied in two ways to drug development, i) to define the pharmacokinetic (PK) properties of labeled drug candidates or ii) to assess the pharmacodynamic (PD) properties of new drugs. Molecular imaging's role in drug discovery and development has grown significantly over the last decade and it will continue to have a major impact on the assessment and profiling of new drugs for the foreseeable future. Since 1975 radioactive labeled entities, small molecules and biologics, have been considered by the United States Food and Drug Administration (FDA) to be drugs and are regulated as such. In spite of the fact that imaging probes, by their very nature, are tracers with minimal mass and no expected pharmacological or toxicological properties, they must undergo extensive safety evaluation prior to approval by the FDA. All human studies involving radioactively labeled molecules, unless exempt, must be performed under FDA guidelines using either an investigational new drug (IND) a or Radioactive Drug Research Committee (RDRC) b approval mechanism. This article describes the United States regulatory pathways that are involved to permit the use of new and existing radiopharmaceuticals in the drug discovery and development process.

Biodistribution and radiation dosimetry of 11C-harmine in baboons

Monoamine oxidase A is a mitochondrial enzyme which is responsible for the metabolism of catecholamines such as dopamine, norepinephrine, as well as serotonin. This study describes the biodistribution and dosimetry of 11C-harmine, a tracer designed to specifically bind to monoamine oxidase A for positron emission tomography imaging. Three baboon studies were acquired using a Seimens ECAT camera. Dynamic whole-body emission scans were collected in two-dimensional mode over a 2 h period after 223-255 MBq of 11C-harmine was injected. Regions of interest were drawn on transmission corrected images to encompass the entire activity in visible organs at each time point. Time-activity data were used to obtain residence times and absorbed radiation dose to various organs and to the entire body. Tracer uptake was greatest in the lungs, followed by kidney, small intestine, liver and brain. The largest absorbed dose based on averaged residence times was found in the lungs (reference adult/female 3.99x10(-2)/5.03x10(-2) mSv x MBq(-1)). The lungs are the critical organs for administration of 11C-harmine. For example, in the United States, the absorbed dose to the lungs would limit a single 11C-harmine administration for a research subject with the approval of a Radioactive Drug Research Committee to 1258/999 MBq (34/27 mCi) in the adult male/female. Quantitative measurement of monoamine oxidase A activity in the brain and elsewhere may aid in understanding the pathophysiology of several disease processes including neuroendocrine neoplasms and depression.

Imaging Update: New Windows, New Views

The recent progress in our understanding of the molecular-genetic mechanisms active in many diseases and the application of new biologically based approaches in therapy are exciting new developments that have emerged following mapping of the human genome. Novel “molecular therapies” have been

Biodistribution and Radiation Dosimetry of the Synthetic Nonmetabolized Amino Acid Analogue Anti-18F-FACBC in Humans

The synthetic leucine amino acid analog anti-1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid (anti-(18)F-FACBC) is a recently developed ligand that permits the evaluation of the L-amino acid transport system. This study evaluated the whole-body radiation burden of anti-(18)F-FACBC in humans. Serial whole-body PET/CT scans of 6 healthy volunteers (3 male and 3 female) were acquired for 2 h after a bolus injection of anti-(18)F-FACBC (366 +/- 51 MBq). Organ-specific time-activity curves were extracted from the reconstructed data and integrated to evaluate the individual organ residence times. A uniform activity distribution was assumed in the body organs with urine collection after the study. Estimates of radiation burden to the human body were calculated on the basis of the recommendations of the MIRD committee. The updated dynamic bladder model was used to calculate dose to the bladder wall. All volunteers showed initially high uptake in the pancreas and liver, followed by rapid clearance. Skeletal muscle and bone marrow showed lower and prolonged uptake, with clearance dominated by the tracer half-life. The liver was the critical organ, with a mean absorbed dose of 52.2 microGy/MBq. The estimated effective dose was 14.1 microSv/MBq, representing less than 20% of the dose limit recommended by the Radioactive Drug Research Committee for a 370-MBq injection. Bladder excretion was low and initially observed 6 min after injection, well after peak tracer uptake in the body organs. The PET whole-body dosimetry estimates indicate that an approximately 370-MBq injection of anti-(18)F-FACBC yields good imaging and acceptable dosimetry. The nonmetabolized nature of this tracer is favorable for extraction of relevant physiologic parameters from kinetic models.

Amyloid plaque imaging agent [C-11]-6-OH-BTA-1: biodistribution and radiation dosimetry in baboon

The amyloid neuritic plaque is considered to be a toxic collection of amyloid-ss protein found in brain tissue in Alzheimer's disease. A neutral analogue of the amyloid-binding thioflavin-T (BTA), has been radiolabeled as [C-11]-6-OH-BTA-1. It crosses the blood brain barrier, and is a promising tracer for imaging plaques in vivo using positron emission tomography. We now report the biodistribution and dosimetry of [C-11]-6-OH-BTA-1 in baboons. Four 2-hour whole body studies were acquired in an ECAT ACCEL camera in two baboons after the bolus injection of [C-11]-6-OH-BTA-1. After 3.5 minute transmission scans performed per bed position prior to injection, emission scans were collected in 2-D mode over five bed positions. Regions of interest (ROI) were drawn around the brain, left and right lungs, heart, liver, gall bladder, left and right kidneys, spleen and urinary bladder. Since no fluid was removed from the baboons, total body radioactivity was calculated using the injected dose and a calibration factor determined from a cylinder phantom. The area under the curve (AUC) for each ROI was determined by trapezoidal integration of the first few points with subsequent points fit by a decreasing monoexponential. The AUC was then divided by counts in the total body, and resulting residence times were entered into the MIRDOSE3 program. The animals tolerated the procedure well. The ligand was eliminated via the hepatobiliary and renal systems. In the adult male and female reference the gallbladder received the highest estimated radiation dose and was the critical organ (3.9E-02 mGy/MBq and 4.3E-02 mGy/MBq respectively). In the United States, the absorbed dose to the gallbladder would limit [C-11]-6-OH-BTA-1 administered with the approval of a Radioactive Drug Research Committee (RDRC) to a single injection of 1295 MBq (35 mCi) in the adult male, and 1314 MBq (35 mCi) in the adult female.

A rational regulatory approach for positron emission tomography imaging probes: from “first in man” to NDA approval and reimbursement

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.

Biodistribution and radiation dosimetry of [ 11C]DASB in baboons

Objective The serotonin transporter has been implicated in a variety of conditions including mood disorders and suicidal behavior. In vivo human brain studies with positron emission tomography and the serotonin transporter antagonist [ 11C]DASB ([ 11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) are ongoing in several laboratories with the maximum administered activity based on dosimetry collected in rodents. We report on the biodistribution and dosimetry of [ 11C]DASB in the baboon as this species may be a more reliable surrogate for human dosimetry. Methods Four baboon studies (two studies in each of two baboons) were acquired in an ECAT ACCEL camera after the bolus injection of 183±5 MBq/2.3±1.0 nmol of [ 11C]DASB. For each study, six whole-body emission scans were collected in 3D mode over 6/7 bed positions for 2 h. Regions of interest were drawn on brain, lungs, liver, gallbladder, spleen, kidneys, small intestine and bladder. Since no fluid was removed from the animal, total body radioactivity was calculated using the injected dose calibrated to the ACCEL image units. Results Uptake was greatest in lungs, followed by the urinary bladder, gallbladder, brain and other organs. The ligand was eliminated via the hepato-billiary and renal systems. The largest absorbed dose was found in the lungs (3.6×10 −2 mSv/MBq). The absorbed radiation doses in lungs and gallbladder were four and nine times larger than that previously estimated from rat studies. Conclusion Based on our baboon biodistribution and dose estimates, the lungs are the critical organs for administration of [ 11C]DASB. In the United States, the absorbed dose to the lungs would limit [ 11C]DASB administered with the approval of a Radioactive Drug Research Committee to 1400 MBq (37 mCi) in the adult male and 1100 MBq (30 mCi) in the adult female.