First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

Autor:	Pieren M; BioVersys AG, Basel, Switzerland., Abáigar Gutiérrez-Solana A; CTI Laboratory Services S.L., Ibaizabal bidea, 702, 48160 Derio, Biscay, Spain., Antonijoan Arbós RM; Institut de Recerca de l'HSCSP, IIB Sant Pau, Centre d'Investigació de Medicaments (CIM), Barcelona, Spain., Boyle GW; GSK, Stevenage, UK., Davila M; BioVersys AG, Basel, Switzerland., Davy M; GSK, Stevenage, UK., Gitzinger M; BioVersys AG, Basel, Switzerland.; BioVersys SAS, Lille, France., Husband L; BioVersys SAS, Lille, France., Martínez-Martínez MS; GSK, Tres Cantos, Spain., Mazarro DO; Clinical Trials Unit, Clinical Pharmacology Department, Facultad de Medicina, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain., Pefani E; GSK, Stevenage, UK., Penman SL; GSK, London, UK., Remuiñán MJ; GSK, Tres Cantos, Spain., Vlasakakis G; GSK, Philadelphia, PA, USA., Zeitlinger M; Department of Clinical Pharmacology, Vienna University Hospital, Medical University of Vienna, Vienna, Austria., Dale GE; BioVersys AG, Basel, Switzerland.; BioVersys SAS, Lille, France.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2024 Jun 03; Vol. 79 (6), pp. 1353-1361.
DOI:	10.1093/jac/dkae107
Abstrakt:	Background: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. Objectives: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). Methods: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. Results: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. Conclusions: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food. (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
Databáze:	MEDLINE
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