Phase I clinical study of NMB58, a novel positron emission tomography (PET)-myocardial perfusion imaging tracer, conducted to evaluate its safety and pharmacokinetics in Japanese healthy adult males

Abstract

NMB58 is a novel positron emission tomography (PET) tracer containing flurpiridaz as an active ingredient and available as a myocardial perfusion imaging tracer that targets mitochondrial complex 1. A phase I clinical study of NMB58 was conducted to evaluate its safety and pharmacokinetics in healthy volunteers. Ten healthy Japanese volunteers received bolus injection of NMB58 (111–167 MBq) intravenously and underwent imaging studies at rest on day 1. Of these subjects, 5 (day 2 cohort 1; exercise stress) and 5 (day 2 cohort 2; pharmacological stress) similarly underwent stress imaging studies on day 2. The safety of NMB58 was evaluated through monitoring of signs/symptoms, electrocardiography, vital signs, and laboratory examinations at baseline and several time points during 3 days. Sequential whole-body positron emission tomography-computed tomography (PET/CT) scan data were acquired for up to 5-h post-injection, with venous blood and urine samples collected for up to 8-h post-injection. Based on the results of the biodistribution study, the absorbed radiation dose (Rad) was estimated by the Medical Internal Radiation Dose method. On day 1, the kidneys were shown to have the highest Rad, followed by the myocardium. On day 2, the myocardium was shown to have the highest Rad, followed by the kidneys. The mean effective doses (EDs) per unit activity administered were 0.021, 0.017 and 0.021 mSv/MBq for overall subjects (day 1), day 2 cohort 1 and day 2 cohort 2, respectively. The estimated exposure dose of NMB58 was similar to or lower than those of radiotracers currently approved for clinical use, including 18F-Fludeoxyglucose. Biodistribution results indicated that NMB58 distributed to the myocardium exhibited high and sustained retention after administration. The cumulative urinary radioactivity excretion rate was shown to be 6.9, 2.3%, and 8.0% of the injected dose in overall subjects (day 1), day 2 cohort 1 and day 2 cohort 2. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Based on radiation dosimetry, biodistribution, and safety evaluations, NMB58 was found to be a suitable tracer for clinical use in PET myocardial perfusion imaging during exercise or pharmacological stress.