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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

dc.contributor.authorZhu, Tongen_ZA
dc.contributor.authorFriedrich, Sven O.en_ZA
dc.contributor.authorDiacon, Andreasen_ZA
dc.contributor.authorWallis, Robert S.en_ZA
dc.date.accessioned2016-06-20T10:02:15Z
dc.date.available2016-06-20T10:02:15Z
dc.date.issued2014
dc.identifier.citationZhu, T., et al. 2014. Population pharmacokinetic/pharmacodynamic nalysis 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. Antimicrobial Agents and Chemotherapy, 58(6): 330-3311
dc.identifier.issn1098-6596 (online)
dc.identifier.issn0066-4804 (print)
dc.identifier.otherdoi: 10.1128/AAC.01920-13
dc.identifier.urihttp://hdl.handle.net/10019.1/99043
dc.descriptionCITATION: Zhu, T., et al. 2014. Population pharmacokinetic/pharmacodynamic nalysis 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. Antimicrobial Agents and Chemotherapy, 58(6): 330-3311, doi: 10.1128/AAC.01920-13.
dc.descriptionThe original publication is available at http://aac.asm.org
dc.description.abstractSutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular Mycobacterium tuberculosis by sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellular M. tuberculosis was 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (−0.269 log10 per day; 90% CI, −0.237 to −0.293 log10 per day) than single daily dosing (−0.186 log10 per day; 90% CI, −0.160 to −0.208 log10 per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations.en_ZA
dc.description.urihttp://aac.asm.org/content/58/6/3306.full
dc.format.extent6 pages
dc.language.isoen_ZAen_ZA
dc.publisherAmerican Society for Microbiology
dc.subjectMycobacterium tuberculosis -- Effect of drugs onen_ZA
dc.subjectSutezolid -- Pharmacokineticsen_ZA
dc.subjectSutezolid -- Physiological effecten_ZA
dc.subjectAnti-infective agentsen_ZA
dc.subjectAntimicrobial drugsen_ZA
dc.subjectMetabolitesen_ZA
dc.titlePopulation 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 tuberculosisen_ZA
dc.typeArticleen_ZA
dc.description.versionPublisher's version
dc.rights.holderAmerican Society for Microbiology


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