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Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-Human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598


Journal Article

Gu, K.; Spitz, R.; Hammett, E.; Jaunarajs, A.; Ghazaryan, V.; Garvey, E. P.; Degenhardt, T.

Med Mycol




Vt-1598 first-in-human study oral dose safety and pharmacokinetics tetrazole antifungal

VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in evaluation of the safety and pharmacokinetic (PK) of single ascending dose of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00 to 279.4 ng/mL and for its primary metabolite, VT-11134, were 27.80 to 108.8 ng/mL. Plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1 to 4507 ng*h/mL, and for VT-11134 were 1140 to 7156 ng*h/mL. The dose proportionality was inconclusive based on the results of power model. The peak concentration time (Tmax) was 4 to 5 hr for VT-1598 and for VT-11134. Half-life was 103 to126 hr for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development. VT-1598 is a tetrazole antifungal with improved selectivity and demonstrated a high survival rate when murine infected with invasive aspergillosis, coccidiodomycosis, cryptococcosis, and candidiasis. We report first-in-human study to evaluate safety and pharmacokinetics after oral dose of VT-1598.

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