Pharmacokinetics, pharmacodynamics and safety of oral formulation (CG-750) of ivaltinostat, a histone deacetylase inhibitor, compared to IV formulation (CG-745).

ABSTRACT

AIMS: CG-750 is an oral formulation of ivaltinostat, a newly developing histone deacetylase (HDAC) inhibitor. This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of an oral formulation (CG-750) of ivaltinostat compared to an intravenous (IV) formulation (CG-745). METHODS: A randomized, double-blind, placebo-controlled study was conducted in three cohorts. Subjects received either CG-745 (Cohorts 1 and 3 125 mg; Cohort 2 250 mg) or placebo followed by CG-750 (Cohort 1 125 mg; Cohort 2 375 mg; Cohort 3 750 mg) or placebo. Blood samples for PK and PD assessment were collected up to 72 h post-dose. Histone H3 acetylation at sites K9, K9/K14 and K27 was assessed for area under the % acetylation induction versus time curve (AUEC). RESULTS: A total of 25 subjects were randomized, and 23 subjects completed the study (Cohort 1, n = 6; Cohort 2, n = 6; Cohort 3, n = 6; placebo, n = 5). The mean bioavailability of CG-750 was 10.6% (range 4.18%-21.33%) and displayed linear PK in the dose range of 125-750 mg. The comparison of AUEC between formulations and the evaluation of the dose-AUEC relationship were inconclusive, due to the small sample sizes and significant variability observed in PD markers. All adverse events (AEs) were transient and of mild or moderate intensity. CONCLUSIONS: The oral formulation of ivaltinostat (CG-750) was generally well tolerated after a single dose. CG-750 displayed a mean bioavailability of 10.6%.