title: Pharmacokinetics of tedizolid in subjects with renal or hepatic impairment.
abstract: Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].).
authors.affiliation: Cubist, San Diego, California, USA shawn.flanagan@cubist.com.
authors.forename: S
authors.initials: S
authors.lastname: Flanagan
authors.affiliation: Minassian Biostatistics, Inc., San Diego, California, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Minassian
authors.affiliation: Covance, Madison, Wisconsin, USA.
authors.forename: D
authors.initials: D
authors.lastname: Morris
authors.affiliation: Covance, Madison, Wisconsin, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ponnuraj
authors.affiliation: Orlando Clinical Research Center, Orlando, Florida, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Marbury
authors.affiliation: DaVita Clinical Research, Minneapolis, Minnesota, USA.
authors.forename: H W
authors.initials: HW
authors.lastname: Alcorn
authors.affiliation: Cubist, San Diego, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Fang
authors.affiliation: Cubist, San Diego, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Prokocimer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000473:pathology*; D008099:Liver / Q000503:physiopathology; D008107:Liver Diseases / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000009:adverse effects / Q000493:pharmacokinetics*; D010080:Oxazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D023303:Oxazolidinones / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics; D006435:Renal Dialysis; D013777:Tetrazoles / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; D011355:Prodrugs; D013777:Tetrazoles; C546016:tedizolid; C515040:tedizolid phosphate