NDLI: Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis▿

Content Provider	PubMed Central
Author	Wallis, Robert S. Jakubiec, Wesley Kumar, Vikas Bedarida, Gabriella Silvia, Annette Paige, Darcy Zhu, Tong Mark, Mitton-fry Lynn, Ladutko Campbell, Sheldon Miller, Paul F.
Copyright Year	2011
Abstract	Tuberculosis is a serious global health threat for which new treatments are urgently needed. This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the oxazolidinone PNU-100480 in healthy volunteers, using biomarkers for safety and efficacy. Subjects were randomly assigned to PNU-100480 or placebo (4:1) at schedules of 100, 300, or 600 mg twice daily or 1,200 mg daily for 14 days or a schedule of 600 mg twice daily for 28 days to which pyrazinamide was added on days 27 and 28. A sixth cohort was given linezolid at 300 mg daily for 4 days. Signs, symptoms, and routine safety tests were monitored. Bactericidal activity against Mycobacterium tuberculosis was measured in ex vivo whole-blood culture. Plasma drug and metabolite concentrations were compared to the levels required for inhibition of M. tuberculosis growth and 50% inhibition of mitochondrial protein synthesis. All doses were safe and well tolerated. There were no hematologic or other safety signals during 28 days of dosing at 600 mg twice daily. Plasma concentrations of PNU-100480 and metabolites at this dose remained below those required for 50% inhibition of mitochondrial protein synthesis. Cumulative whole-blood bactericidal activity of PNU-100480 at this dose (−0.316 ± 0.04 log) was superior to the activities of all other doses tested (P < 0.001) and was significantly augmented by pyrazinamide (−0.420 ± 0.06 log) (P = 0.002). In conclusion, PNU-100480 was safe and well tolerated at all tested doses. Further studies in patients with tuberculosis are warranted. Biomarkers can accelerate early development of new tuberculosis treatments.
Related Links	http://dx.doi.org/10.1128/AAC.01179-10
Starting Page	567
File Format	PDF
ISSN	10986596
e-ISSN	10986596
Journal	Antimicrobial Agents and Chemotherapy
Issue Number	2
Volume Number	55
Language	English
Publisher	American Society for Microbiology (ASM)
Publisher Date	2011-02-01
Access Restriction	Open
Rights Holder	American Society for Microbiology (ASM)
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Pharmacology Pharmacology (medical)

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Susceptibility of Clinical Mycobacterium tuberculosis Isolates to a Potentially Less Toxic Derivate of Linezolid, PNU-100480▿

Promising Antituberculosis Activity of the Oxazolidinone PNU-100480 Relative to That of Linezolid in a Murine Model▿

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis

Pharmacokinetics and Whole-Blood Bactericidal Activity against Mycobacterium tuberculosis of Single Doses of PNU-100480 in Healthy Volunteers

Efficacy and Safety of Metronidazole for Pulmonary Multidrug-Resistant Tuberculosis

Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

Early Bactericidal Activity of High-Dose Rifampin in Patients with Pulmonary Tuberculosis Evidenced by Positive Sputum Smears▿

Efficacy of Antimicrobial Peptoids against Mycobacterium tuberculosis ▿

Fast Standardized Therapeutic-Efficacy Assay for Drug Discovery against Tuberculosis▿

Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis▿

Similar Documents

Susceptibility of Clinical Mycobacterium tuberculosis Isolates to a Potentially Less Toxic Derivate of Linezolid, PNU-100480▿

Promising Antituberculosis Activity of the Oxazolidinone PNU-100480 Relative to That of Linezolid in a Murine Model▿

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis

Pharmacokinetics and Whole-Blood Bactericidal Activity against Mycobacterium tuberculosis of Single Doses of PNU-100480 in Healthy Volunteers

Efficacy and Safety of Metronidazole for Pulmonary Multidrug-Resistant Tuberculosis

Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

Early Bactericidal Activity of High-Dose Rifampin in Patients with Pulmonary Tuberculosis Evidenced by Positive Sputum Smears▿

Efficacy of Antimicrobial Peptoids against Mycobacterium tuberculosis ▿

Fast Standardized Therapeutic-Efficacy Assay for Drug Discovery against Tuberculosis▿

Biomarker-Assisted Dose Selection for Safety and Efficacy in Early Development of PNU-100480 for Tuberculosis▿