Comparison of High-Specific-Activity Ultratrace <sup>123/131</sup>I-MIBG and Carrier-Added <sup>123/131</sup>I-MIBG on Efficacy, Pharmacokinetics, and Tissue Distribution

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A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of 123 Iiobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. Methods: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. Results: A reference clinical imaging database acquired over time for healthy men and women injected with highspecific-activity 123 I-iobenguane showed organ distribution and whole-body retention similar to those of conventional 123 I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. Conclusion: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity 123 I-iobenguane.Key Words: iobenguane 123 I; MIBG; human dosimetry; high specific activity; human distribution J Nucl Med 2014; 55: 765-771 DOI: 10.2967/jnumed.113.124057 Iobenguane,ormet aiodobenzylguanidine (MIBG), is a guanethidine derivative functionally resembling norepinephrine. The drug guanethidine was developed in 1960 and was once a mainstay for the treatment of hypertension (1). It is no longer used in the United States; however, it is still licensed in some countries for the rapid control of blood pressure in a hypertensive emergency and as an intravenous nerve-blocking agent to treat chronic regional pain. Iobenguane and guanethidine are substrates for the norepinephrine transporter (NET) and accumulate by the uptake 1 mechanism into presynaptic nerve endings. Unlike norepinephrine, these drugs are protonated under physiologic conditions; therefore, they do not cross the blood-brain barrier and in vivo uptake is limited primarily to systemic neuronal tissue (2,3). In this paradigm, with chronic administration excess iobenguane can inhibit the neuroendocrine response in hypertensive patients, but with intravenous administration it can cause a hypertensive response often identified as iobenguane-associated adverse events.In healthy adults, the tissue density of systemic NET receptors is highest in the presynaptic neurons innervating myocytes (4). The accumulation of iobenguane in myocardial tissue is also dictated by the high fraction of aortic blood flow that enters the coronary arteries. This physiology constitutes an ideal molecular targeting mechanism for diagnosis of various cardiac diseases, including heart failure, heart transplant rejection, ischemic heart disease, dysautonomia, and drug-induced cardiotoxicity, as well as cardiac neuropathy related to diabetes mellitus and Parkinson disease (5-7). If a substantial fraction of the receptors are occupied by nonradioactive substrates, the overall uptake of radioactiv...

Section: Hsa 123 I-iobenguane Test Articlementioning

confidence: 99%

Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free ¹²³I-Iobenguane

Chin

Kronauge²,

Femia³

et al. 2014

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“…With the standard synthesis of 131 I-MIBG, only approximately 1/2,000 MIBG molecules are radioactive (specific activity,~1.2 MBq/mg), whereas the others continue to bear noncytotoxic 127 I (11). Cold carrier MIBG molecules in the infusion solution potentially can diminish uptake in target organs and neuroblastoma.…”

mentioning

confidence: 99%

Dose Escalation Study of No-Carrier-Added ¹³¹I-Metaiodobenzylguanidine for Relapsed or Refractory Neuroblastoma: New Approaches to Neuroblastoma Therapy Consortium Trial

Matthay¹,

Weiss²,

Villablanca³

et al. 2012

and 14 Molecular Insight Pharmaceuticals, Cambridge, Massachusetts 131 I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%-37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of 131 I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of nocarrier-added (NCA) 131 I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response. Methods: Eligible patients were 1-30 y old with resistant neuroblastoma, 131 I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA 131 I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA 131 I-MIBG (specific activity, 165 MBq/mg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA 131 I-MIBG was escalated from 444 to 777 MBq/kg (12-21 mCi/kg) using a 3 1 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/mL within 28 d or platelets to greater than 20,000/mL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. Four of 15 patients had a complete (n 5 1) or partial (n 5 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease. Conclusion: NCA 131 I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.

“…Plasma normetanephrine and total metanephrine levels decreased from greater than 20,000 and 40,000 pg/mL, respectively, at baseline to 14,295 and 14,329 pg/mL, respectively, at 13 wk after treatment. NET-TARGETED THERANOSTICS • Pandit-Taskar and Modak (122). A phase 1 study of non-carrier-added 123 I-MIBG showed favorable dosimetry and safety.…”

Section: Strategies For Improving Net Targeting and Dose Delivery Witmentioning

confidence: 99%

Norepinephrine Transporter as a Target for Imaging and Therapy

Pandit‐Taskar

Modak

2017

The norepinephrine transporter (NET) is essential for norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. In neuroendocrine tumors, NET can be targeted for imaging as well as therapy. One of the most widely used theranostic agents targeting NET is metaiodobenzylguanidine (MIBG), a guanethidine analog of norepinephrine. 123 I/ 131 I-MIBG theranostics have been applied in the clinical evaluation and management of neuroendocrine tumors, especially in neuroblastoma, paraganglioma, and pheochromocytoma. 123 I-MIBG imaging is a mainstay in the evaluation of neuroblastoma, and 131 I-MIBG has been used for the treatment of relapsed high-risk neuroblastoma for several years, however, the outcome remains suboptimal. 131 I-MIBG has essentially been only palliative in paraganglioma/pheochromocytoma patients. Various techniques of improving therapeutic outcomes, such as dosimetric estimations, high-dose therapies, multiple fractionated administration and combination therapy with radiation sensitizers, chemotherapy, and other radionuclide therapies, are being evaluated. PET tracers targeting NET appear promising and may be more convenient options for the imaging and assessment after treatment. Here, we present an overview of NET as a target for theranostics; review its current role in some neuroendocrine tumors, such as neuroblastoma, paraganglioma/ pheochromocytoma, and carcinoids; and discuss approaches to improving targeting and theranostic outcomes.