First-in-Human Imaging with 89Zr-Df-IAB2M Anti-PSMA Minibody in Patients with Metastatic Prostate Cancer: Pharmacokinetics, Biodistribution, Dosimetry, and Lesion Uptake.

We conducted a phase I dose-escalation study with 89Zr-desferrioxamine-IAB2M (89Zr-IAB2M), an anti-prostate-specific membrane antigen minibody, in patients with metastatic prostate cancer. METHODS: Patients received 185 MBq (5 mCi) of 89Zr-IAB2M and Df-IAB2M at total mass doses of 10 (n = 6), 20 (n = 6), and 50 mg (n = 6). Whole-body and serum clearance, normal-organ and lesion uptake, and radiation absorbed dose were estimated, and the effect of mass escalation was analyzed. RESULTS: Eighteen patients were injected and scanned without side effects. Whole-body clearance was monoexponential, with a median biologic half-life of 215 h, whereas serum clearance showed biexponential kinetics, with a median biologic half-life of 3.7 (12.3%/L) and 33.8 h (17.9%/L). The radiation absorbed dose estimates were 1.67, 1.36, and 0.32 mGy/MBq to liver, kidney, and marrow, respectively, with an effective dose of 0.41 mSv/MBq (1.5 rem/mCi). Both skeletal and nodal lesions were detected with 89Zr-IAB2M, most visualized by 48-h imaging. CONCLUSION: 89Zr-IAB2M is safe and demonstrates favorable biodistribution and kinetics for targeting metastatic prostate cancer. Imaging with 10 mg of minibody mass provides optimal biodistribution, and imaging at 48 h after injection provides good lesion visualization. Assessment of lesion targeting is being studied in detail in an expansion cohort.

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.