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

Shawn Flanagan, Edward E. McKee, Debaditya Das, Paul M. Tulkens, Hiromi Hosako, Jill Fiedler-Kelly, Julie Passarell, Ann Radovsky, Philippe Prokocimer

Research output: Contribution to journalArticle

45 Citations (Scopus)

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 μMversus 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 tedi-zolid-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.

Original languageEnglish (US)
Pages (from-to)178-185
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Linezolid
Mitochondrial Proteins
Pharmacokinetics
Oxazolidinones
Inhibitory Concentration 50
Therapeutics
Cell Fractionation
Heart Mitochondria
Lactic Acidosis
Mitochondria
Macrophages
Placebos

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function. / Flanagan, Shawn; McKee, Edward E.; Das, Debaditya; Tulkens, Paul M.; Hosako, Hiromi; Fiedler-Kelly, Jill; Passarell, Julie; Radovsky, Ann; Prokocimer, Philippe.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 1, 01.01.2015, p. 178-185.

Research output: Contribution to journalArticle

Flanagan, S, McKee, EE, Das, D, Tulkens, PM, Hosako, H, Fiedler-Kelly, J, Passarell, J, Radovsky, A & Prokocimer, P 2015, 'Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function', Antimicrobial Agents and Chemotherapy, vol. 59, no. 1, pp. 178-185. https://doi.org/10.1128/AAC.03684-14
Flanagan, Shawn ; McKee, Edward E. ; Das, Debaditya ; Tulkens, Paul M. ; Hosako, Hiromi ; Fiedler-Kelly, Jill ; Passarell, Julie ; Radovsky, Ann ; Prokocimer, Philippe. / Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function. In: Antimicrobial Agents and Chemotherapy. 2015 ; Vol. 59, No. 1. pp. 178-185.
@article{4ee0a0bfae3d4ebd86364d895fac0036,
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 μMversus 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 tedi-zolid-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.",
author = "Shawn Flanagan and McKee, {Edward E.} and Debaditya Das and Tulkens, {Paul M.} and Hiromi Hosako and Jill Fiedler-Kelly and Julie Passarell and Ann Radovsky and Philippe Prokocimer",
year = "2015",
month = "1",
day = "1",
doi = "10.1128/AAC.03684-14",
language = "English (US)",
volume = "59",
pages = "178--185",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Nonclinical and pharmacokinetic assessments to evaluate the potential of tedizolid and linezolid to affect mitochondrial function

AU - Flanagan, Shawn

AU - McKee, Edward E.

AU - Das, Debaditya

AU - Tulkens, Paul M.

AU - Hosako, Hiromi

AU - Fiedler-Kelly, Jill

AU - Passarell, Julie

AU - Radovsky, Ann

AU - Prokocimer, Philippe

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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 μMversus 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 tedi-zolid-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.

AB - 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 μMversus 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 tedi-zolid-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.

UR - http://www.scopus.com/inward/record.url?scp=84920142409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920142409&partnerID=8YFLogxK

U2 - 10.1128/AAC.03684-14

DO - 10.1128/AAC.03684-14

M3 - Article

VL - 59

SP - 178

EP - 185

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 1

ER -