PMID- 37269076
OWN - NLM
STAT- MEDLINE
DCOM- 20230605
LR  - 20230613
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 11
IP  - 3
DP  - 2023 Jun
TI  - A phase I, first-in-human study investigating the safety, tolerability, and 
      pharmacokinetics of the maturation inhibitor GSK3739937.
PG  - e01093
LID - 10.1002/prp2.1093 [doi]
LID - e01093
AB  - We report the safety and pharmacokinetic properties of the HIV-1 maturation 
      inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, 
      first-in-human, double-blind, randomized, placebo-controlled, single- (part 1) 
      and multiple- (part 2) dose escalation study with an additional open-label 
      relative bioavailability and food effect study (part 3). Participants received 
      oral ascending single doses (10-800 mg) in part 1, up to 18 once-daily 25- to 
      100-mg or 3 once-weekly 500-mg doses in part 2, and single 100-mg doses as 
      powder-in-bottle or tablet (in fed and fasted states) formulations in part 3. 
      Primary and secondary objectives were safety and pharmacokinetic assessments, 
      respectively. Ninety-one participants were enrolled; 38 reported 81 total adverse 
      events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and 
      resolved during the study. Most drug-related AEs were gastrointestinal (14/17, 
      82%). The terminal phase half-life of GSK'937 was ~3 days for all doses following 
      single and repeat dosing. Geometric mean maximum concentration and total drug 
      exposures exhibited dose-proportional increases during part 1. Accumulation in 
      exposure following repeat dosing was 6- to 7-fold with daily dosing and ~1.7-fold 
      after weekly treatment, as expected due to the long half-life. Bioavailability of 
      GSK'937 after a meal was 1.35- to 1.40-fold greater as a tablet versus 
      powder-in-bottle and >2-fold higher in fed versus fasted states when provided as 
      a tablet. No unexpected or dose-limiting safety events occurred. Pharmacokinetic 
      parameters of long half-life and accumulation of exposure following repeat dosing 
      suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: 
      NCT04493684.
CI  - (c) 2023 ViiV Healthcare. Pharmacology Research & Perspectives published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society and American 
      Society for Pharmacology and Experimental Therapeutics.
FAU - Benn, Paul D
AU  - Benn PD
AUID- ORCID: 0009-0007-1117-6385
AD  - ViiV Healthcare, Brentford, UK.
FAU - Zhang, Ying
AU  - Zhang Y
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Kahl, Lesley
AU  - Kahl L
AD  - ViiV Healthcare, Brentford, UK.
FAU - Greene, Thomas J
AU  - Greene TJ
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Bainbridge, Veronica
AU  - Bainbridge V
AD  - GSK, Brentford, UK.
FAU - Fishman, Cindy
AU  - Fishman C
AUID- ORCID: 0000-0003-2842-9063
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Wen, Bo
AU  - Wen B
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Gartland, Martin
AU  - Gartland M
AD  - ViiV Healthcare, Durham, North Carolina, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT04493684
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 (Powders)
RN  - 0 (Tablets)
SB  - IM
MH  - Humans
MH  - *Powders
MH  - Administration, Oral
MH  - Biological Availability
MH  - Area Under Curve
MH  - Tablets
PMC - PMC10238757
OTO - NOTNLM
OT  - HIV-1 maturation inhibitor
OT  - bioavailability
OT  - dose escalation
OT  - first-in-human
OT  - food effect
EDAT- 2023/06/03 11:42
MHDA- 2023/06/05 06:42
PMCR- 2023/06/02
CRDT- 2023/06/03 01:02
PHST- 2023/02/28 00:00 [received]
PHST- 2023/03/15 00:00 [accepted]
PHST- 2023/06/05 06:42 [medline]
PHST- 2023/06/03 11:42 [pubmed]
PHST- 2023/06/03 01:02 [entrez]
PHST- 2023/06/02 00:00 [pmc-release]
AID - PRP21093 [pii]
AID - 10.1002/prp2.1093 [doi]
PST - ppublish
SO  - Pharmacol Res Perspect. 2023 Jun;11(3):e01093. doi: 10.1002/prp2.1093.