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 non-human 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 ng/mL and 436,000 ng/mL and area-under-the-curve exposure values of 130,000 hr*ng/mL and 1,240,000 hr*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.
Background
Biopharmaceutical development necessitates use of nonhuman primates in toxicology, leading to adoption of nontraditional methods including cognitive function assessment.
Methods
A two-object discrimination and reversal test in cynomolgus monkeys (Macaca fascicularis) was performed using a Wisconsin General Testing Apparatus (WGTA). Nonclinical study design and regulatory considerations dictate that infants are raised by their biological mothers until weaning at six months. Thirty four animals (six to 21 months of age) were trained to discriminate between two randomly selected stimulus objects to retrieve a reward. Following training, days to first reversal after interchanging the reward were measured.
Results
Both sexes acquired visual discrimination skills at similar rates. Trends in learning and reversals completed were uniform across age groups. Completing training early in some subjects had no impact on subsequent testing phases.
Conclusion
Weaned cynomolgus monkey infants can be successfully tested for cognitive abilities using the WGTA in a nonclinical laboratory setting.
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