Trial reportBritish journal of clinical pharmacology2022
A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.
Trial report in British journal of clinical pharmacology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03426995 (A Randomised, Double-blind), which is not on this map. Cited by 5 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Randomised, Double-blind (Sponsor Open), Placebo-controlled, Three Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699 in Healthy Male Participants
Who cites it
5 citing papers in PubMed.
- A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.British journal of clinical pharmacology · 2022Trial
- Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024Review
- Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review).Oncology reports · 2024Article
- Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.British journal of clinical pharmacology · 2022Article
- Article
Corrections and comments
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Authors and funding
19 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsGSK3358699 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).
methodsPart 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.
resultsIn 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.
conclusionsSingle 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.
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