Elsevier

Journal of Nuclear Cardiology

Volume 26, Issue 6, December 2019, Pages 2018-2030
Journal of Nuclear Cardiology

Original Article
Dosimetry, biodistribution, and safety of flurpiridaz F 18 in healthy subjects undergoing rest and exercise or pharmacological stress PET myocardial perfusion imaging

https://doi.org/10.1007/s12350-018-01484-zGet rights and content

Abstract

The objectives of this study were to evaluate radiation dosimetry, biodistribution, human safety, and tolerability of 18F-labeled flurpiridaz (Flurpiridaz) in normal subjects undergoing rest and separate-day exercise or adenosine pharmacological stress PET imaging.

Methods

12 normal subjects were injected with 58.5 to 121 MBq (1.58 to 3.27 mCi) of Flurpiridaz intravenously at rest on Day 1 and 57 to 171 MBq (1.54 to 4.61 mCi) during stress on Day 2. Sequential whole-body imaging was performed for 5 hours. Blood samples were collected for up to 8 hours.

Results

The heart wall received the largest mean absorbed dose with both exercise and adenosine stresses. The mean effective dose was 0.054 rem/mCi (0.015 mSv/MBq) with exercise and 0.069 rem/mCi (0.019 mSv/MBq) with adenosine pharmacological stress. The maximum dose that may be administered without exceeding 1 rem (10 mSv) effective dose was 19 mCi (685 MBq) for exercise and 15 mCi (539 MBq) for adenosine pharmacological stress. There were no drug-related adverse events, and the tracer was well tolerated in all subjects.

Conclusion

Based on radiation dosimetry, biodistribution, and safety observations, 18F-labeled flurpiridaz is found suitable for clinical PET myocardial perfusion imaging in conjunction with either exercise or pharmacological stress testing.

Introduction

Flurpiridaz F 18 (Flurpiridaz), formerly BMS747158, is a novel 18F-labeled PET myocardial perfusion imaging (MPI) tracer that is a structural analog of pyridaben and binds to mitochondrial complex 1 (MC-1) with high affinity1 (Figure 1). As mitochondria constitute from 20% to 30% of the myocardial intracellular volume, molecules that target mitochondrial proteins are selectively retained in the myocardium with a high density.2 Preclinical studies showed superior myocardial extraction and prolonged retention of Flurpiridaz compared with SPECT MPI tracers.1,3, 4, 5 Thus, Flurpiridaz has the potential to yield steady-state myocardial imaging with the improved resolution and quantitation afforded by PET. Flurpiridaz also could provide improved clinical utility and ease of use because of the longer half-life of 18 F (110 minutes) that makes delivery of unit doses from regional PET pharmacies feasible.

In the first-in-human study of Flurpiridaz, dosimetry, biodistribution, and safety of this tracer were evaluated after a single-dose injection at rest.6 The organ receiving the largest mean absorbed dose was the kidneys followed by the heart wall. Furthermore, after resting injection of Flurpiridaz, it was found that the heart exhibited high and sustained retention of radioactivity from the earliest images through approximately 5 hours after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects.

The objectives of this study were to estimate the radiation dosimetry, biodistribution, safety, and tolerability of Flurpiridaz in healthy subjects undergoing either treadmill exercise or adenosine pharmacological stress in conjunction with 2-day rest/stress PET MPI.

Section snippets

Study Population

This study was approved by the institutional review boards at both centers (David Geffen School of Medicine at the University of California, Los Angeles; and The Johns Hopkins Medical Institutions, Baltimore, Maryland) ,and all patients signed informed consent before any procedures. Twelve healthy adults (as determined by medical history, physical examination, vital signs, ECG, EEG, neurological examination, and clinical laboratory testing), ages from 22 to 37 years, participated in the study.

Radiation Dosimetry

The critical organ for Flurpiridaz when administered during exercise stress was the heart wall with a mean estimated dose of 0.15 rem/mCi (0.039 mSv/MBq) (Table 1). The critical organ for Flurpiridaz when administered during adenosine stress was also the heart wall with a mean estimated dose of 0.33 rem/mCi (0.090 mSv/MBq) (Table 2). The mean ED for Flurpiridaz was 0.054 rem/mCi (0.015 mSv/MBq) for exercise stress (Table 3) and was 0.069 rem/mCi (0.019 mSv/MBq) for adenosine stress (Table 4).

Discussion

In this study, we evaluated dosimetry, biodistribution, pharmacokinetics, safety and tolerability of two doses of Flurpiridaz in normal subjects undergoing either exercise or adenosine pharmacological stress in conjunction with 2-day rest-stress PET myocardial perfusion imaging.

For dosimetry assessments, accuracy of radioisotope measurement is a paramount concern. As such, we used 2D acquisition mode at both sites for the dosimetry imaging since there were suggestions in the literature that 2D

Study Limitations

Although the study population was typical for a Phase 1 study, its characteristics were different from the population of patients referred for clinically indicated PET MPI; they were mostly men, were healthy, had low BMI and took no medications. It is expected that young and healthy subjects have higher organ blood flow and mitochondrial density, yielding a higher organ uptake of Flurpiridaz than older and diseased patients. Therefore, our biodistribution measurements represent “the worst-case

Conclusion

Stress PET myocardial perfusion imaging is feasible with 18F-labeled flurpiridaz injected in conjunction with either treadmill exercise or pharmacological stress testing. Dosimetry of this tracer is within the clinically acceptable range. 18F-labeled flurpiridaz was found to be safe and well tolerated.

New Knowledge Gained

18F-labeled flurpiridaz can be conveniently used for PET myocardial perfusion imaging in conjunction with either pharmacological stress or treadmill exercise. This radiotracer has a favorable dosimetry, consistent with current clinical radionuclide imaging guidelines. 18F-labeled flurpiridaz, injected during stress, was found to be safe and well tolerated in this small population of normal subjects.

Acknowledgements

The authors wish to acknowledge the assistances of Jean-Richard Eugene, CNMT in PET image acquisition and processing, Deborah Dorsey, RN, and Parham Naghdechi, MD in the recruitment and monitoring of the research subjects. The authors are grateful to Susan Ramsey for analyzing the data and for helpful comments on drafts of the manuscript. Financial support for this study was provided by Lantheus Medical Imaging, Billerica, MA.

Disclosure

Jamshid Maddahi is the Chair of the Steering Committee, Member of the

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    Funding for this study was provided by Lantheus Medical Imaging, Billerica, MA.

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