Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers

The Journal of Infectious Diseases
Robert S WallisPaul F Miller

Abstract

The oxazolidinone PNU-100480 is superior to linezolid against experimental murine tuberculosis. Two metabolites contribute to but do not fully account for its superiority. This study examined the safety, tolerability, pharmacokinetics, and mycobactericidal activity of single ascending doses of PNU-100480. Nineteen healthy volunteers received 2 escalating single oral doses (35-1500 mg) of PNU-100480 or placebo. Eight subjects received 4 daily doses of 300 mg of linezolid. Drug concentrations and bactericidal activity against Mycobacterium tuberculosis in whole-blood bactericidal culture were measured. All doses were safe and well tolerated. PNU-100480 doses to 1000 mg were well absorbed and showed approximately proportional increases in exposures of parent and metabolites. The geometric mean maximal concentrations of PNU-100480, PNU-101603, and PNU-101244 (sulfoxide and sulfone metabolites) at 1000 mg were 839, 3558, and 54 ng/mL, respectively. The maximal whole-blood bactericidal activity (-0.37 +/- .06 log/day) occurred at combined PNU levels > or =2 times the minimum inhibitory concentration. The observed geometric mean maximal concentration for linezolid was 6425 ng/mL. Its maximal whole-blood bactericidal activity also occu...Continue Reading

Citations

May 19, 2011·The Journal of Antibiotics·Mark S Butler, Matthew A Cooper
Sep 5, 2013·The Journal of Antibiotics·Mark S ButlerMatthew A Cooper
May 1, 2013·Nature Reviews. Drug Discovery·Alimuddin ZumlaStewart T Cole
Mar 8, 2012·The Journal of Infectious Diseases·Hazel M Dockrell
Jul 19, 2012·The Journal of Infectious Diseases·Kelly E DooleyUNKNOWN Efficacy Subgroup, RESIST-TB
Oct 19, 2012·The Journal of Antimicrobial Chemotherapy·Juan Carlos Palomino, Anandi Martin
Jun 16, 2010·Respirology : Official Journal of the Asian Pacific Society of Respirology·Eric L NuermbergerWing Wai Yew
Apr 4, 2012·Antimicrobial Agents and Chemotherapy·Kathy WilliamsEric L Nuermberger
May 8, 2013·Antimicrobial Agents and Chemotherapy·Kwok-Chiu ChangRaphael Chiu-Yeung Chan
Nov 17, 2010·Antimicrobial Agents and Chemotherapy·Robert S WallisPaul F Miller
Jun 29, 2011·Future Microbiology·Claudia Sala, Ruben C Hartkoorn
Jul 26, 2012·Future Microbiology·Katherine A SackstederCarol A Nacy
Oct 9, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Robert S Wallis
Sep 1, 2014·European Journal of Medicinal Chemistry·Giovanna PoceMariangela Biava
Feb 16, 2012·Expert Opinion on Pharmacotherapy·Michael Lauzardo, Charles A Peloquin
Mar 7, 2014·Expert Opinion on Drug Metabolism & Toxicology·Jonathan Reynolds, Scott K Heysell
Nov 19, 2015·Expert Opinion on Investigational Drugs·Yong-Soo Kwon, Won-Jung Koh
Aug 9, 2011·Current Opinion in Microbiology·Stewart T Cole, Giovanna Riccardi
Oct 28, 2015·Future Medicinal Chemistry·Deepak KumarDiwan S Rawat
Dec 24, 2011·Annals of the New York Academy of Sciences·Karen Joy Shaw, Michael R Barbachyn
May 10, 2016·Tuberculosis·Elizabeth P HarauszUNKNOWN TB Research Unit (TBRU) at Case Western Reserve University
Sep 27, 2015·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Marco SchitoAlimuddin Zumla
May 5, 2011·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Mandeep S Jassal, Grace M Aldrovandi
Oct 22, 2014·Antimicrobial Agents and Chemotherapy·Rokeya TasneenEric L Nuermberger
Apr 3, 2016·The Lancet Infectious Diseases·Robert S WallisAlimuddin Zumla
Nov 28, 2013·Pharmaceuticals·Olivia PerwitasariRalph A Tripp
Mar 26, 2014·Antimicrobial Agents and Chemotherapy·Ming ZhangStewart T Cole
Mar 10, 2016·Antimicrobial Agents and Chemotherapy·Gaëlle Guiewi MakafeTianyu Zhang
Nov 18, 2010·Drugs·Ann M Ginsberg
May 6, 2015·ERJ Open Research·Lia D'AmbrosioGiovanni Battista Migliori
Jun 30, 2019·Medicinal Research Reviews·Aparna Bahuguna, Diwan S Rawat
Mar 13, 2014·Current Opinion in Pulmonary Medicine·Yong-Soo KwonWon-Jung Koh
Apr 9, 2020·BMC Microbiology·Philip Kam Weng KwanNicholas I Paton
Oct 9, 2013·Current Opinion in HIV and AIDS·Kelly E DooleyAndreas H Diacon
Mar 14, 2019·Current Opinion in Pulmonary Medicine·Simon F K LeeMarc Lipman
Dec 13, 2019·The Cochrane Database of Systematic Reviews·Angeline G GraceRichard Kirubakaran
Aug 18, 2016·Expert Review of Anti-infective Therapy·Sean WassermanGary Maartens
Jul 15, 2021·Journal of Medicinal Chemistry·Qianqian ZhaoWenqiang Cao
Feb 26, 2020·Journal of Medicinal Chemistry·Matthew A CernyGregory S Walker

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.