Pharmacokinetics of tedizolid, sutezolid, and sutezolid-M1 in non-human primates

Sarah Kim, Charles A. Scanga, Carolina de Miranda Silva, Matthew Zimmerman, Chelsea Causgrove, Brianne Stein, Véronique Dartois, Charles A. Peloquin, Emily Graham, Arnold Louie, Jo Anne L. Flynn, Stephan Schmidt, George L. Drusano

Research output: Contribution to journalArticlepeer-review

Abstract

Non-human primates (NHP) are thought to be a good preclinical animal model for tuberculosis because they develop disease characteristics that are similar to humans. The objective of the current study was to determine if NHPs can also be used to reliably predict the exposure of tedizolid, sutezolid, and its biologically active metabolite sutezolid-M1 in humans. The prodrug tedizolid phosphate and sutezolid were administered orally to NHPs either once or twice daily for up to eight days. The active moieties, tedizolid, and sutezolid showed linear pharmacokinetics and respective concentration-time profiles could be described by one-compartment body models with first-order elimination. One additional metabolite compartment with first-order elimination was found appropriate to capture the pharmacokinetics of sutezolid-M1. Once allometrically scaled to humans with a fixed exponent of 0.75 for apparent clearance and 1 for apparent volume of distribution, the AUCs of tedizolid and sutezolid were predicted reasonably well, whereas Cmax was under-predicted for sutezolid. Both NHP and humanized concentration-time profiles will now be used in vitro hollow-fiber pharmacodynamic experiments to determine if differences in drug exposures result in differences in Mycobacterium tuberculosis kill and emergence of resistance.

Original languageEnglish (US)
Article number105421
JournalEuropean Journal of Pharmaceutical Sciences
Volume151
DOIs
StatePublished - Aug 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Keywords

  • Non-human primate
  • Pharmacokinetics
  • Sutezolid
  • Tedizolid

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