title: Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function.
abstract: 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.
authors.affiliation: Cubist Pharmaceuticals, San Diego, California, USA shawn.flanagan@cubist.com.
authors.forename: Shawn
authors.initials: S
authors.lastname: Flanagan
authors.affiliation: College of Medicine, Central Michigan University, Mount Pleasant, Michigan, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: McKee
authors.affiliation: Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Debaditya
authors.initials: D
authors.lastname: Das
authors.affiliation: Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Paul M
authors.identifier: http://orcid.org/0000-0002-7121-3623
authors.initials: PM
authors.lastname: Tulkens
authors.affiliation: WIL Research, Ashland, Ohio, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hosako
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Fiedler-Kelly
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Passarell
authors.affiliation: WIL Research, Ashland, Ohio, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Radovsky
authors.affiliation: Cubist Pharmaceuticals, San Diego, California, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Prokocimer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D000069349:Linezolid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009010:Monte Carlo Method; D020258:Neurotoxicity Syndromes / Q000209:etiology; D023303:Oxazolidinones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D020332:Rats, Inbred LEC; D013777:Tetrazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D036401:Toxicity Tests, Chronic / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D024101:Mitochondrial Proteins; D023303:Oxazolidinones; D013777:Tetrazoles; C546016:tedizolid; D000069349:Linezolid