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

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).

Fig. 1.

Chemical structures of Galeterone (1), VNPP433-3β (2), VNPT-155 (3) and VNPP414 (4)

Fig. 2:

Mean body weights of nude mice (A) following treated with one bolus of compound 2 and (B) during chronic dosing of compound 2. Note: * It should be noted that one mouse died in the 100 mg/kg group and the mean body weight in this group was of two mice. ns = not significant.

Fig. 3:

Mean body weights of CD-1 mice on day 0, 1, 2 and 3 following treatments (oral gavage, PO) with three doses of compound 2. * Note: For the group dosed with 1000 mg.kg of compound 2, two mice died on days 2 and the third mice died on day 3.

Fig. 4.

Concentration vs. time profiles of compound 2 dosed intravenously to (A) female and (B) male rats at 1 mg/kg. Note: * LLOQ = lower limit of quantification.

Fig. 5.

Concentration vs. time profiles of compound 2 dosed orally to female and male rats at 10 mg/kg (A and B) or 50 mg/kg (C and D). Note: * LLOQ = lower limit of quantification.