PMID- 33200887
OWN - NLM
STAT- MEDLINE
DCOM- 20210903
LR  - 20240330
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 8
IP  - 6
DP  - 2020 Dec
TI  - Phase I evaluation of the safety, tolerability, and pharmacokinetics of 
      GSK3640254, a next-generation HIV-1 maturation inhibitor.
PG  - e00671
LID - 10.1002/prp2.671 [doi]
LID - e00671
AB  - Despite advances in HIV-1 management with antiretroviral therapy, drug resistance 
      and toxicities with multidrug regimens can result in treatment failure. Hence, 
      there is a continuing demand for antiretroviral agents (ARVs) with novel 
      mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a 
      unique mechanism of action and can be combined with other ARVs. Two phase I 
      randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, 
      to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability 
      (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 
      1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 
      participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In 
      Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo 
      (n = 14). Four participants reported adverse events (AEs) leading to study 
      discontinuation, with one adverse drug reaction (maculopapular rash). There was 
      no relationship between frequency or severity of AEs and dose. Pharmacokinetic 
      assessments showed that GSK3640254 was slowly absorbed, with time to maximum 
      concentration (tmax) occurring between 3.5 and 4 hours and half-life 
      of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt 
      vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt 
      performed slightly better than the bis-hydrochloride formulation (12%-16% 
      increase in area under the concentration-time curve and maximum concentration); 
      tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and 
      safety data from these healthy-participant studies informed further development 
      of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection.
CI  - (c) 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley 
      & Sons Ltd, British Pharmacological Society and American Society for Pharmacology 
      and Experimental Therapeutics.
FAU - Joshi, Samit R
AU  - Joshi SR
AUID- ORCID: 0000-0002-1332-5918
AD  - ViiV Healthcare, Branford, CT, USA.
FAU - Fernando, Disala
AU  - Fernando D
AD  - GlaxoSmithKline Clinical Unit Cambridge, Cambridge, UK.
FAU - Igwe, Stephanie
AU  - Igwe S
AD  - GlaxoSmithKline Clinical Unit Cambridge, Cambridge, UK.
FAU - McKenzie, Litza
AU  - McKenzie L
AD  - Quotient Sciences, Nottingham, UK.
FAU - Krishnatry, Anu S
AU  - Krishnatry AS
AD  - GlaxoSmithKline, Upper Providence, PA, USA.
FAU - Halliday, Fiona
AU  - Halliday F
AD  - GlaxoSmithKline, Stockley Park, UK.
FAU - Zhan, Joyce
AU  - Zhan J
AD  - GlaxoSmithKline, Upper Providence, PA, USA.
FAU - Greene, Thomas J
AU  - Greene TJ
AD  - GlaxoSmithKline, Upper Providence, PA, USA.
FAU - Xu, Jianfeng
AU  - Xu J
AD  - GlaxoSmithKline, Upper Providence, PA, USA.
FAU - Ferron-Brady, Geraldine
AU  - Ferron-Brady G
AD  - GlaxoSmithKline, Upper Providence, PA, USA.
FAU - Lataillade, Max
AU  - Lataillade M
AD  - ViiV Healthcare, Branford, CT, USA.
FAU - Min, Sherene
AU  - Min S
AD  - ViiV Healthcare, Research Triangle Park, NC, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03231943
SI  - ClinicalTrials.gov/NCT03575962
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 (Anti-Retroviral Agents)
RN  - 0 (HIV-1 maturation inhibitor EP39)
RN  - 0 (Succinates)
RN  - 0 (Triterpenes)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anti-Retroviral Agents/chemistry/*pharmacokinetics/*therapeutic use
MH  - Cohort Studies
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - HIV Infections/diagnosis/*drug therapy/metabolism
MH  - HIV-1/*drug effects/metabolism
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Succinates/chemistry/*pharmacology/*therapeutic use
MH  - Triterpenes/chemistry/*pharmacology/*therapeutic use
MH  - Young Adult
PMC - PMC7670640
OTO - NOTNLM
OT  - HIV-1 infection
OT  - bioavailability
OT  - clinical study
OT  - first-time-in-human
OT  - healthy participants
OT  - pharmacokinetics
OT  - safety
COIS- Samit R. Joshi, Max Lataillade, and Sherene Min are employees of ViiV Healthcare; 
      Max Lataillade and Sherene Min own stock in GlaxoSmithKline (GSK). Disala 
      Fernando, Stephanie Igwe, Anu S. Krishnatry, Fiona Halliday, Joyce Zhan, Thomas 
      J. Greene, Jianfeng Xu, and Geraldine Ferron-Brady are employees of GSK and own 
      stock in GSK. Litza McKenzie is an employee of Quotient Sciences, which was 
      contracted by GSK to perform the clinical aspects of the relative bioavailability 
      study, and she served as the principal investigator; Dr McKenzie receives a fixed 
      wage from Quotient Sciences, which is not dependent on the conduct or outcome of 
      any individual study.
EDAT- 2020/11/18 06:00
MHDA- 2021/09/04 06:00
PMCR- 2020/11/17
CRDT- 2020/11/17 08:43
PHST- 2020/07/31 00:00 [received]
PHST- 2020/09/14 00:00 [revised]
PHST- 2020/09/21 00:00 [accepted]
PHST- 2020/11/17 08:43 [entrez]
PHST- 2020/11/18 06:00 [pubmed]
PHST- 2021/09/04 06:00 [medline]
PHST- 2020/11/17 00:00 [pmc-release]
AID - PRP2671 [pii]
AID - 10.1002/prp2.671 [doi]
PST - ppublish
SO  - Pharmacol Res Perspect. 2020 Dec;8(6):e00671. doi: 10.1002/prp2.671.