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Regul Toxicol Pharmacol. 2018 Dec;100:59-67. doi: 10.1016/j.yrtph.2018.10.009. Epub 2018 Oct 22.

Intravenous toxicity and toxicokinetics of an HDL mimetic, Fx-5A peptide complex, in cynomolgus monkeys.

Author information

1
National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA.
2
National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
3
National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA. Electronic address: tersep@mail.nih.gov.

Abstract

Fx-5A peptide complex (Fx-5A), a High Density Lipoproteins (HDL) mimetic, has been shown to reduce atherosclerosis. The safety and toxicokinetics of Fx-5A administered IV by 30 min infusion at 8, 25 or 75 mg/kg body weight or vehicle, once every other day for 27 days, were assessed in cynomolgus monkeys. The Fx-5A was well tolerated at all doses. At the highest dose, there were statistically significant effects on hematology and clinical chemistry parameters that were considered non-adverse. Dose-dependent recoverable non-adverse erythrocytes morphological changes (acanthocytes, echinocytes, spherocytes, microcytes, and/or schistocytes) were observed. Fx-5A was not hemolytic in in-vitro fresh NHP or human blood assay. There were no Fx-5A-related statistically significant changes for any cardiovascular function, ECG or respiratory parameters, when compared to control. In addition, there were no Fx-5A-related effects on organ weights, macroscopic or microscopic endpoints. Finally, Fx-5A exhibited sporadic non-appreciable detection of anti-Fx-5A antibodies and a dose-dependent linear toxicokinetics with T1/2 value ranges from 2.7 to 6.2 h. In conclusion, the No Observed Adverse Effect Level was considered to be 75 mg/kg/day with associated exposures average Cmax and AUC0-last of 453 μg/mL and 2232 h μg/mL, respectively, on Day 27.

KEYWORDS:

Atherosclerosis; Cynomolgus monkeys; Fx-5A peptide complex; HDL mimetic; Safety

PMID:
30359697
DOI:
10.1016/j.yrtph.2018.10.009
[Indexed for MEDLINE]

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