PMID- 37621050
OWN - NLM
STAT- MEDLINE
DCOM- 20231229
LR  - 20240305
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 90
IP  - 1
DP  - 2024 Jan
TI  - Pharmacokinetics and tolerability of the maturation inhibitor GSK3640254 
      coadministered with darunavir/ritonavir and/or etravirine in healthy adults.
PG  - 274-285
LID - 10.1111/bcp.15893 [doi]
AB  - AIMS: This phase I study investigated potential drug-drug interactions of the 
      maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) 
      and/or etravirine (ETR). METHODS: In this randomized, open-label, 
      single-sequence, multiple-dose study, healthy participants received GSK'254 
      200 mg once daily alone or coadministered with DRV/RTV 600/100 mg twice daily 
      (BID; n = 19), ETR 200 mg BID (n = 19) or DRV/RTV 600/100 mg + ETR 200 mg BID 
      (n = 16) under fed conditions. Primary endpoints were steady-state area under the 
      plasma concentration-time curve from time 0 to the end of the dosing interval 
      (AUC(0-tau) ) and maximum observed concentration (C(max) ). Secondary endpoints 
      included trough concentration (C(tau) ), safety and tolerability. Pharmacokinetic 
      parameters were calculated using standard noncompartmental analysis, and 
      geometric least-squares mean ratios were derived from linear mixed-effects 
      models. RESULTS: GSK'254 AUC(0-tau) (geometric least-squares mean ratio [90% 
      confidence interval], 1.14 [1.00-1.29]), C(max) (1.07 [0.92-1.24]) and C(tau) (1.17 
      [1.01-1.35]) were similar when administered alone and with DRV/RTV. Etravirine 
      coadministration decreased GSK'254 AUC(0-tau) (0.53 [0.48-0.59]), C(max) (0.60 
      [0.53-0.68]) and C(tau) (0.51 [0.39-0.66]). Similar reductions were not observed 
      with GSK'254 + DRV/RTV + ETR (AUC(0-tau) , 0.94 [0.82-1.09]; C(max) , 0.89 
      [0.75-1.07]; C(tau) , 1.02 [0.89-1.18]). GSK'254 had no meaningful effect on 
      DRV/RTV or ETR concentrations. All reported adverse events (AEs) were grade 1; 3 
      led to withdrawal and resolved (rash, asymptomatic electrocardiogram T-wave 
      inversion, periorbital oedema). Most common AEs were diarrhoea (n = 9) and 
      headache (n = 7). No deaths or serious AEs occurred. CONCLUSION: GSK'254 
      pharmacokinetics was not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but 
      were reduced with only ETR; no new tolerability concerns were observed.
CI  - (c) 2023 ViiV Healthcare. British Journal of Clinical Pharmacology published by 
      John Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Zhang, Ying
AU  - Zhang Y
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Joshi, Samit
AU  - Joshi S
AD  - ViiV Healthcare, Branford, Connecticut, USA.
FAU - Yazdani, Parto
AU  - Yazdani P
AD  - GSK, Mississauga, Ontario, Canada.
FAU - Zhan, Joyce
AU  - Zhan J
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Wen, Bo
AU  - Wen B
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Bainbridge, Veronica
AU  - Bainbridge V
AD  - GSK, Brentford, UK.
FAU - Ballesteros-Perez, Alex
AU  - Ballesteros-Perez A
AD  - Certara, Princeton, New Jersey, USA.
FAU - Gartland, Martin
AU  - Gartland M
AD  - ViiV Healthcare, Durham, North Carolina, USA.
FAU - Lataillade, Max
AU  - Lataillade M
AD  - ViiV Healthcare, Branford, Connecticut, USA.
LA  - eng
GR  - ViiV Healthcare/
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230920
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - YO603Y8113 (Darunavir)
RN  - O3J8G9O825 (Ritonavir)
RN  - 0C50HW4FO1 (etravirine)
RN  - 0 (Anti-HIV Agents)
RN  - 0 (GSK3640254)
RN  - 0 (Sulfonamides)
SB  - IM
MH  - Adult
MH  - Humans
MH  - Darunavir
MH  - *Ritonavir
MH  - *Anti-HIV Agents
MH  - Sulfonamides
MH  - Drug Interactions
OTO - NOTNLM
OT  - HIV/AIDS
OT  - antiretrovirals
OT  - cytochrome P450
OT  - drug interactions
OT  - phase I
EDAT- 2023/08/25 06:42
MHDA- 2023/12/29 06:43
CRDT- 2023/08/25 00:43
PHST- 2023/08/04 00:00 [revised]
PHST- 2023/03/31 00:00 [received]
PHST- 2023/08/09 00:00 [accepted]
PHST- 2023/12/29 06:43 [medline]
PHST- 2023/08/25 06:42 [pubmed]
PHST- 2023/08/25 00:43 [entrez]
AID - 10.1111/bcp.15893 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2024 Jan;90(1):274-285. doi: 10.1111/bcp.15893. Epub 2023 
      Sep 20.