PMID- 29226626
OWN - NLM
STAT- MEDLINE
DCOM- 20180727
LR  - 20210109
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 5
IP  - 6
DP  - 2017 Dec
TI  - Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of 
      RIPK1 inhibitor GSK2982772 in healthy volunteers.
LID - 10.1002/prp2.365 [doi]
LID - e00365
AB  - GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 
      1 (RIPK1) being developed to treat chronic inflammatory diseases. This 
      first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and 
      exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy 
      male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind 
      study. In Part A, subjects received single ascending doses of GSK2982772 
      (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods. 
      In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to 
      up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open-label 
      relative bioavailability study comparing 20-mg tablets vs capsules. Safety, 
      tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and 
      pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were 
      contact dermatitis and headache. Most AEs were mild in intensity, and there were 
      no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the 
      dose range studied (up to 120 mg BID). There was no evidence of drug accumulation 
      upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24-hour period 
      for the 60-mg and 120-mg BID dosing regimens. Single and repeat doses of 
      GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The 
      high levels of RIPK1 TE support progression into Phase II clinical trials for 
      further clinical development.
CI  - (c) 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley 
      & Sons Ltd, British Pharmacological Society and American Society for Pharmacology 
      and Experimental Therapeutics.
FAU - Weisel, Kathleen
AU  - Weisel K
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Scott, Nicola E
AU  - Scott NE
AD  - GlaxoSmithKline, Stevenage, UK.
FAU - Tompson, Debra J
AU  - Tompson DJ
AD  - GlaxoSmithKline, Stevenage, UK.
FAU - Votta, Bartholomew J
AU  - Votta BJ
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Madhavan, Sujith
AU  - Madhavan S
AD  - GlaxoSmithKline, Cambridge, UK.
FAU - Povey, Kat
AU  - Povey K
AD  - GlaxoSmithKline, Stevenage, UK.
FAU - Wolstenholme, Allen
AU  - Wolstenholme A
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Simeoni, Monica
AU  - Simeoni M
AD  - GlaxoSmithKline, Stevenage, UK.
FAU - Rudo, Todd
AU  - Rudo T
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Richards-Peterson, Lauren
AU  - Richards-Peterson L
AD  - GlaxoSmithKline, Stevenage, UK.
FAU - Sahota, Tarjinder
AU  - Sahota T
AD  - GlaxoSmithKline, Cambridge, UK.
FAU - Wang, J Gene
AU  - Wang JG
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Lich, John
AU  - Lich J
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Finger, Joshua
AU  - Finger J
AUID- ORCID: 0000-0003-3240-9778
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Verticelli, Adeline
AU  - Verticelli A
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Reilly, Michael
AU  - Reilly M
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Gough, Peter J
AU  - Gough PJ
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Harris, Philip A
AU  - Harris PA
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Bertin, John
AU  - Bertin J
AD  - GlaxoSmithKline, Collegeville, PA, USA.
FAU - Wang, Mei-Lun
AU  - Wang ML
AUID- ORCID: 0000-0003-2735-9833
AD  - GlaxoSmithKline, Collegeville, PA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02302404
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pharmacol Res Perspect
JT  - Pharmacology research & perspectives
JID - 101626369
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Small Molecule Libraries)
RN  - EC 2.7.11.1 (RIPK1 protein, human)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Protein Kinase Inhibitors/*administration & dosage/pharmacokinetics
MH  - Receptor-Interacting Protein Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Small Molecule Libraries/*administration & dosage/pharmacokinetics
MH  - Young Adult
PMC - PMC5723699
OTO - NOTNLM
OT  - GSK2982772
OT  - RIPK1
OT  - anti-inflammatory agents
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - safety
EDAT- 2017/12/12 06:00
MHDA- 2018/07/28 06:00
PMCR- 2017/10/26
CRDT- 2017/12/12 06:00
PHST- 2017/09/18 00:00 [received]
PHST- 2017/09/25 00:00 [accepted]
PHST- 2017/12/12 06:00 [entrez]
PHST- 2017/12/12 06:00 [pubmed]
PHST- 2018/07/28 06:00 [medline]
PHST- 2017/10/26 00:00 [pmc-release]
AID - PRP2365 [pii]
AID - 10.1002/prp2.365 [doi]
PST - ppublish
SO  - Pharmacol Res Perspect. 2017 Dec;5(6):e00365. doi: 10.1002/prp2.365.