PMID- 38263733
OWN - NLM
STAT- MEDLINE
DCOM- 20240329
LR  - 20240329
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 90
IP  - 4
DP  - 2024 Apr
TI  - Pharmacokinetics, pharmacodynamics and safety of oral formulation (CG-750) of 
      ivaltinostat, a histone deacetylase inhibitor, compared to IV formulation 
      (CG-745).
PG  - 1103-1114
LID - 10.1111/bcp.15997 [doi]
AB  - 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%.
CI  - (c) 2024 British Pharmacological Society.
FAU - Kim, Byungwook
AU  - Kim B
AUID- ORCID: 0000-0003-4032-6112
AD  - Department of Clinical Pharmacology and Therapeutics, Seoul National University 
      College of Medicine and Hospital, Seoul, Republic of Korea.
FAU - Huh, Ki Young
AU  - Huh KY
AUID- ORCID: 0000-0002-1872-9954
AD  - Department of Clinical Pharmacology and Therapeutics, Seoul National University 
      College of Medicine and Hospital, Seoul, Republic of Korea.
FAU - Yu, Kyung-Sang
AU  - Yu KS
AUID- ORCID: 0000-0003-0921-7225
AD  - Department of Clinical Pharmacology and Therapeutics, Seoul National University 
      College of Medicine and Hospital, Seoul, Republic of Korea.
FAU - Lee, SeungHwan
AU  - Lee S
AUID- ORCID: 0000-0002-1713-9194
AD  - Department of Clinical Pharmacology and Therapeutics, Seoul National University 
      College of Medicine and Hospital, Seoul, Republic of Korea.
LA  - eng
GR  - CrystalGenomics Pharmaceutical Company/
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20240123
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Histone Deacetylase Inhibitors)
SB  - IM
MH  - Humans
MH  - *Histone Deacetylase Inhibitors/adverse effects
MH  - Area Under Curve
MH  - Dose-Response Relationship, Drug
MH  - Administration, Intravenous
MH  - Biological Availability
MH  - Double-Blind Method
OTO - NOTNLM
OT  - anticancer drugs
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - phase I
EDAT- 2024/01/24 06:43
MHDA- 2024/03/29 06:47
CRDT- 2024/01/24 02:04
PHST- 2023/12/18 00:00 [revised]
PHST- 2023/08/22 00:00 [received]
PHST- 2023/12/27 00:00 [accepted]
PHST- 2024/03/29 06:47 [medline]
PHST- 2024/01/24 06:43 [pubmed]
PHST- 2024/01/24 02:04 [entrez]
AID - 10.1111/bcp.15997 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2024 Apr;90(4):1103-1114. doi: 10.1111/bcp.15997. Epub 2024 
      Jan 23.