title: 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.
abstract: Sutezolid (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.
authors.affiliation: Pfizer, Groton, Connecticut, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Sven O
authors.initials: SO
authors.lastname: Friedrich
authors.affiliation: Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Andreas
authors.initials: A
authors.lastname: Diacon
authors.affiliation: Pfizer, Groton, Connecticut, USA rswallis@gmail.com.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011153:Population; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy / Q000382:microbiology*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D023303:Oxazolidinones; C543015:PNU-100480