1. Antimicrob Agents Chemother. 2015 Jan;59(1):178-85. doi: 10.1128/AAC.03684-14.
Epub 2014 Oct 20.

Nonclinical and pharmacokinetic assessments to evaluate the potential of
tedizolid and linezolid to affect mitochondrial function.

Flanagan S(1), McKee EE(2), Das D(3), Tulkens PM(3), Hosako H(4), Fiedler-Kelly
J(5), Passarell J(5), Radovsky A(4), Prokocimer P(6).

Author information: 
(1)Cubist Pharmaceuticals, San Diego, California, USA shawn.flanagan@cubist.com. 
(2)College of Medicine, Central Michigan University, Mount Pleasant, Michigan,
USA. (3)Louvain Drug Research Institute, Université Catholique de Louvain,
Brussels, Belgium. (4)WIL Research, Ashland, Ohio, USA. (5)Cognigen Corporation, 
Buffalo, New York, USA. (6)Cubist Pharmaceuticals, San Diego, California, USA.

Prolonged treatment with the oxazolidinone linezolid is associated with
myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by 
impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of
the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and 
pharmacokinetic assessments were conducted. In isolated rat heart mitochondria,
tedizolid inhibited MPS more potently than did linezolid (average [± standard
error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μM 
versus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and
high-dose tedizolid (resulting in steady-state area under the plasma
concentration-time curve values about 8-fold greater than those with the standard
therapeutic dose in humans) showed no evidence of neuropathy. Additional studies 
explored why prolonged, high-dose tedizolid did not cause these
mitochondriopathic side effects despite potent MPS inhibition by tedizolid.
Murine macrophage (J774) cell fractionation studies found no evidence of a stable
association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations
based on population pharmacokinetic models showed that over the course of a
dosing interval using standard therapeutic doses, free plasma concentrations fell
below the respective MPS IC50 in 84% of tedizolid-treated patients (for a median 
duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration 
of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow
for mitochondrial recovery during antibacterial therapy. The overall results
suggest that tedizolid has less potential to cause myelosuppression and
neuropathy than that of linezolid during prolonged treatment courses. This,
however, remains a hypothesis that must be confirmed in clinical studies.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PMID: 25331703  [PubMed - in process]