Article ; Online: Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.
International journal of toxicology
2017 Volume 36, Issue 2, Page(s) 104–112
Abstract: BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. ... ...
| Abstract | BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials. |
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| MeSH term(s) | Animals ; Complement System Proteins/analysis ; Dogs ; Drug Hypersensitivity/blood ; Female ; Fluorescent Dyes/pharmacokinetics ; Fluorescent Dyes/toxicity ; HEK293 Cells ; Histamine/blood ; Humans ; Indocyanine Green/analogs & derivatives ; Indocyanine Green/pharmacokinetics ; Indocyanine Green/toxicity ; Macaca fascicularis ; Male ; Mice ; Neoplasms/diagnostic imaging ; Neoplasms/metabolism ; Rats, Sprague-Dawley ; Scorpion Venoms/blood ; Scorpion Venoms/pharmacokinetics ; Scorpion Venoms/toxicity | |||||
| Chemical Substances | Fluorescent Dyes ; Scorpion Venoms ; Histamine (820484N8I3) ; tozuleristide (835UH424TU) ; Complement System Proteins (9007-36-7) ; Indocyanine Green (IX6J1063HV) | |||||
| Language | English | |||||
| Publishing date | 2017-03-17 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 1379845-5 | |||||
| ISSN | 1092-874X ; 1091-5818 | |||||
| ISSN (online) | 1092-874X | |||||
| ISSN | 1091-5818 | |||||
| DOI | 10.1177/1091581817697685 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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