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A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.
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- Author(s): Brown JA;Brown JA; Bal J; Bal J; Simeoni M; Simeoni M; Williams P; Williams P; Mander PK; Mander PK; Soden PE; Soden PE; Daga S; Daga S; Fahy WA; Fahy WA; Wong GK; Wong GK; Bloomer JC; Bloomer JC; Erwig L; Erwig L; Erwig L; Cui Y; Cui Y; Fernando D; Fernando D; Carnaghan H; Carnaghan H; Banham-Hall EJ; Banham-Hall EJ; Hopkins S; Hopkins S; Davis BG; Davis BG; Oliveira JJD; Oliveira JJD; Prinjha RK; Prinjha RK
- Source:
British journal of clinical pharmacology [Br J Clin Pharmacol] 2022 May; Vol. 88 (5), pp. 2140-2155. Date of Electronic Publication: 2021 Dec 18.- Publication Type:
Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't- Language:
English - Source:
- Additional Information
- Source: Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 7503323 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2125 (Electronic) Linking ISSN: 03065251 NLM ISO Abbreviation: Br J Clin Pharmacol Subsets: MEDLINE
- Publication Information: Publication: Oxford : Wiley-Blackwell
Original Publication: London, Macmillan Journals Ltd. - Subject Terms:
- Abstract: Aims: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995).
Methods: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts.
Results: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization.
Conclusions: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.
(© 2021 GlaxoSmithKline. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.) - References: Br J Clin Pharmacol. 2022 May;88(5):2140-2155. (PMID: 34773923)
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Med Res Rev. 2021 Jan;41(1):223-245. (PMID: 32926459) - Contributed Indexing: Keywords: GSK3358699; bromodomain and extra-terminal domain; epigenetic reader protein; myeloid; pharmacodynamics; pharmacokinetics
- Molecular Sequence: ClinicalTrials.gov NCT03426995
- Publication Date: Date Created: 20211113 Date Completed: 20220412 Latest Revision: 20220731
- Publication Date: 20240104
- Accession Number: PMC9300116
- Accession Number: 10.1111/bcp.15137
- Accession Number: 34773923
- Source:
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