Next tier in vitro and in vivo nonclinical studies further elucidating the safety and toxicity profile of MB-102, a novel fluorescent tracer agent for measurement of glomerular filtration rate

• Published in: Regulatory toxicology and pharmacology Vol. 107; p. 104417
• Main Authors: Dorshow, Richard B., Bugaj, Joseph E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2019
• Subjects: Animals; BALB 3T3 Cells; Contrast Media - pharmacokinetics; Dermatitis, Phototoxic; Dogs; Drug Interactions; Female; Fluorescence; Fluorescent Dyes - pharmacokinetics; Fluorescent Dyes - toxicity; Fluorescent tracer agent; Glomerular Filtration Rate; Iohexol - pharmacokinetics; Male; Mice; Mice, Nude; Micronucleus Tests; Optical monitoring; Preclinical evaluation; Pyrazine; Pyrazines - pharmacokinetics; Pyrazines - toxicity; Rabbits; Rats, Sprague-Dawley; Renal clearance; Renal function; Safety and toxicity profile; Preclinical evaluation; Renal function; Optical monitoring; Pyrazine; Renal clearance; Fluorescence; Fluorescent tracer agent; Safety and toxicity profile; Glomerular filtration rate
• ISSN: 0273-2300; 1096-0295; 1096-0295
• DOI: 10.1016/j.yrtph.2019.104417

MB-102 was designed for measurement of real-time glomerular filtration rate (GFR). Previously reported in vitro and in vivo nonclinical studies clearly demonstrated negligible toxicity, resulting in FDA clearance for First-in Human, proof of concept clinical studies. The next tier of safety and toxicity studies are reported herein. MB-102 did not demonstrate any phototoxic potential in a BALB/c 3T3 mouse fibroblast study. Co-administration of MB-102 and iohexol resulted in pharmacokinetic parameters virtually identical to the values observed upon individual administration in beagle dogs. A single dose of MB-102 administered either intravenously (18.6 mg/mL) or perivenously (0.25 mL) was well-tolerated in NZ white rabbits, with no adverse inflammation or irritation. MB-102 did not induce micronuclei in polychromatic erythrocytes for rat bone marrow cells treated up to 450 mg/kg/day, the maximum feasible dose. Two separate optical imaging studies demonstrated that MB-102 distributes rapidly and thoroughly throughout the test subjects, followed by rapid clearance from the body without any preferential localization in any particular tissue or organ, with the exception of the bladder, which is totally consistent with a known GFR agent. In addition, two-week repeat intravenous (once-daily) toxicity and toxicokinetic studies were conducted in rats and beagles, with no MB-102- related effects. Thus, for the studies reported herein, there were no toxicological effects of concern for MB-102. •MB-102 is not phototoxic, genotoxic, and did not interact with iohexol in vivo.•In vivo, MB-102 distributes quickly, clears rapidly, and localizes only in the bladder, as expected of a GFR tracer agent.•Two week repeat intravenous studies in rat and beagle show no abnormal test article effects.•MB-102 is safe for advancement in on-going human clinical studies for real-time point-of-care GFR measurement.