Murine toxicology and pharmacokinetics of lead next generation galeterone analog, VNPP433-3β

Elizabeth Thomas; Retheesh S Thankan; Puranik Purushottamachar; Jianxia Guo; Robert A Parise; Jan H Beumer; Vincent C O Njar

doi:10.1016/j.steroids.2023.109184

Murine toxicology and pharmacokinetics of lead next generation galeterone analog, VNPP433-3β

Steroids. 2023 Apr:192:109184. doi: 10.1016/j.steroids.2023.109184. Epub 2023 Jan 24.

Authors

Elizabeth Thomas¹, Retheesh S Thankan², Puranik Purushottamachar¹, Jianxia Guo³, Robert A Parise³, Jan H Beumer⁴, Vincent C O Njar⁵

Affiliations

¹ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
² Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Isoprene Pharmaceuticals, Inc., 801 W. Baltimore Street, Suite 502J, Baltimore, MD 21201, USA.
³ Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
⁴ Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA 15261, USA; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: beumerjh@upmc.edu.
⁵ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Isoprene Pharmaceuticals, Inc., 801 W. Baltimore Street, Suite 502J, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Electronic address: VNjar@som.umaryland.edu.

Abstract

VNPP433-3β (compound 2, (3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). Compound 2 is currently in development as potential new therapeutic for prostate and pancreatic cancers. The preliminary toxicity study reveals that the compound 2 was better tolerated by the normal male CD-1 mice than the male Nude mice. The maximum tolerated dose (MTD) in the Nude mice was estimated to be between 25 < 50 mg/kg. After oral dosing of compound 2 to male and female rats, the plasma concentration versus time curves were very consistent between animals and the AUC_last increased with dose. Many plasmas concentration versus time curves profiles were nearly flat over 24 hr., suggesting extended absorption from the GI tract. Consequently, reliable values for half-life and AUC_inf were not determined. Calculated oral bioavailability (using oral AUC_last and excluding the outlier IV animal) ranged from 32 to 47 %. This should be considered a minimum value since the contribution to true AUC beyond 24 hr. is clearly not zero. Clearly, these toxicology and pharmacokinetics parameters pave the way for understanding the anticancer pharmacological actions and provide a meaningful basis for further preclinical development and eventual clinical development.

Keywords: Anti-prostate cancer agent; Oral bioavailability; Pharmacokinetics; Toxicology; VNPP433-3β (2).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Androstadienes / pharmacology
Animals
Antineoplastic Agents* / toxicity
Benzimidazoles / pharmacology
Female
Male
Mice
Mice, Nude
Rats

Substances

3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
Antineoplastic Agents
Benzimidazoles
Androstadienes

Abstract

Publication types

MeSH terms

Substances

Grants and funding