title: Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis.
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.
authors.affiliation: Pfizer, Groton-New London, CT 06320, USA. robert.wallis@pfizer.com
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
authors.forename: Wesley
authors.initials: W
authors.lastname: Jakubiec
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bedarida
authors.forename: Annette
authors.initials: A
authors.lastname: Silvia
authors.forename: Darcy
authors.initials: D
authors.lastname: Paige
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Mark
authors.initials: M
authors.lastname: Mitton-Fry
authors.forename: Lynn
authors.initials: L
authors.lastname: Ladutko
authors.forename: Sheldon
authors.initials: S
authors.lastname: Campbell
authors.forename: Paul F
authors.initials: PF
authors.lastname: Miller
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D000069349:Linezolid; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011718:Pyrazinamide / Q000494:pharmacology; D051381:Rats; D015610:Serum Bactericidal Test; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D055815:Young Adult
chemical_list: D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; C543015:PNU-100480; D011718:Pyrazinamide; D000069349:Linezolid