Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo controlled First Time in Human study in healthy volunteers - Fernando - - British Journal of Clinical Pharmacology - Wiley Online LibraryBritish Journal of Clinical PharmacologyAccepted Articles SHORT COMMUNICATION Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo controlled First Time in Human study in healthy volunteers Disala Fernando, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorRichard Dimelow, orcid.org/0000-0003-1246-5705 GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorCiara Gorey, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorXinyi Zhu, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorCatherine Muya, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorConnie Parker, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorWayne Wright, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorSara Soleman, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorSarah Walsh, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorMadelein Crause, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorGeorgios Vlasakakis, orcid.org/0000-0002-7390-9712 GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorWilliam Guiney, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorNicola Robertson, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorMarylise Bergeal, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorYi Cui, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorAlex Krug, Now at Vertex Pharmaceuticals, Boston, MA, USASearch for more papers by this authorIain Uings, Corresponding Author iain.j.uings@gsk.com Disala Fernando, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorRichard Dimelow, orcid.org/0000-0003-1246-5705 GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorCiara Gorey, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorXinyi Zhu, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorCatherine Muya, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorConnie Parker, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorWayne Wright, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorSara Soleman, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorSarah Walsh, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorMadelein Crause, Clinical Unit Cambridge, Addenbrookes Centre for Clinical Investigation, Cambridge, United KingdomSearch for more papers by this authorGeorgios Vlasakakis, orcid.org/0000-0002-7390-9712 GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorWilliam Guiney, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorNicola Robertson, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorMarylise Bergeal, GlaxoSmithKline David Jack Centre, Park Road, Ware, Hertfordshire, United KingdomSearch for more papers by this authorYi Cui, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, United KingdomSearch for more papers by this authorAlex Krug, Now at Vertex Pharmaceuticals, Boston, MA, USASearch for more papers by this authorIain Uings, Corresponding Author iain.j.uings@gsk.com This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.15010. Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URLShare a linkShare onEmailFacebookTwitterLinked InRedditWechat 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 20.6L and 44.6L, a clearance between 0.462L/h and 0.805L/hr and a terminal half-life between 31.3 and 34.5hr. In the single subject who received 1.3mg 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 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. Supplementary Table 1. PK and PD model parameter estimates fitted to the observed data from the single subject who received 1.3 mg GSK3335065. Supplementary Table 2 Non-Compartmental Pharmacokinetic Parameters Data is reported for 0.25 and 1.3mg doses only (see methods),. For two subjects in the 0.25 mg treatment group the terminal phase could not be reliably calculated (see methods), so the AUC(0-inf), CL, Vss and t1/2 were not reported and the sample size for the statistical summary (n=4) is smaller than the cohort size (N=6). Supplementary table 3 – Change from Baseline KYN and 3HK levels in cohort 1 & 2 Levels of KYN and 3HK in subjects given 0.1 mg and 0.25 mg GSK3335065 appeared quite variable. Levels of these metabolites in samples from subjects in these cohorts given PBO were not determined and while this error confounds clear interpretation of the data, there appears to be no evidence of pharmacodynamic activity. Figure S1. 2-compartmental PK model used to describe the kinetics of GSK3335065 Figure S2. Indirect response model used to describe the response of KYN in response to GSK3335065. Figure S3. Indirect response model used to describe the response of 3HK in response to GSK3335065. Figure S4. Indirect response model used to describe the response of KYNA in response to GSK3335065 via the effect on KYN levels. Figure S5 Participant flow through the study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. Please check your email for instructions on resetting your password. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account. Can\'t sign in? Forgot your username? Enter your email address below and we will send you your username If the address matches an existing account you will receive an email with instructions to retrieve your username