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Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo‐controlled first‐in‐human study in healthy volunteers
- Source :
- British Journal of Clinical Pharmacology. 88:865-870
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection to assess safety, tolerability, pharmacokinetics and pharmacodynamics. GSK3335065 displayed an apparent volume of distribution between 20.6 L and 44.6 L, a clearance between 0.462 L/h and 0.805 L/hr and a terminal half-life between 31.3 and 34.5 hr. In the single subject who received 1.3 mg GSK3335065, changes in tryptophan pathway metabolites were observed consistent with the changes seen in preclinical species suggesting that KMO enzyme activity was partially inhibited. However, a broad complex ventricular tachycardia was observed in this subject, which was judged to be a Serious Adverse Event (SAE) and resulted in early termination of the study. While development of GSK3335065 was subsequently discontinued, significant confounding factors hinder a clear interpretation that the tachycardia was directly related to administration of the compound.
- Subjects :
- Male
Tachycardia
Pharmacology
Ventricular tachycardia
Placebo
Mixed Function Oxygenases
chemistry.chemical_compound
Double-Blind Method
Pharmacokinetics
Humans
Medicine
Pharmacology (medical)
Adverse effect
Kynurenine
Volume of distribution
business.industry
medicine.disease
Healthy Volunteers
Pancreatitis
Tolerability
chemistry
Acute Disease
medicine.symptom
business
Subjects
Details
- ISSN :
- 13652125 and 03065251
- Volume :
- 88
- Database :
- OpenAIRE
- Journal :
- British Journal of Clinical Pharmacology
- Accession number :
- edsair.doi.dedup.....7a33ecb7f572aef6fad5cd2778c8950f