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 (ϳ8% 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 (ϳ9% 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].)

Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

“…This is supported by results from noncompartmental analyses using richly sampled PK data from subjects with hepatic or renal impairment (including subjects requiring hemodialysis), reported in the companion piece to this article (18). Of note, those noncompartmental analyses showed increases in geometric mean tedizolid AUCs of 22% and 34% in subjects with moderate and severe hepatic impairment, respectively, compared with those of matched controls (18).…”

Tedizolid Adsorption and Transmembrane Clearance during in vitro Continuous Renal Replacement Therapy

“…After supernatant evaporation under nitrogen, the residue was reconstituted and analyzed using high-power liquid chromatography (1200 series; Agilent Technologies, Santa Clara, Calif., USA) with tandem mass spectrometric detection, following a previously validated method [6] . The response from calibration standards was linear ranging from 5 to 1,000 μg/ml with the coefficient of correlation of ≥ 0.998.…”

Reduction in Tedizolid Plasma Exposure among End-Stage Renal Disease Patients Undergoing Dialysis Is Explained by Variations in Ideal Body Weight

“…Detailed methodology and results of this study have been published previously (clinicaltrials.gov registration number NCT01452828) (7). For subjects in the ESRD group, we limited the analysis to PK data obtained when tedizolid was infused postdialysis (although any potential impact of hemodialysis on tedizolid exposure was previously shown to be negligible [7]). The mean (standard deviation) AUC 0 ϱ values were 23.27 (7.50) g · h/ml in the ESRD group, 29.99 (8.97) g · h/ml in the severe renal impairment, and 32.43 (9.53) g · h/ml in the control group.…”

“…Our group recently presented results from a phase 1 study suggesting that tedizolid exposure was about 25% lower in end-stage renal disease (ESRD) patients than in severely renally impaired subjects and matched controls (7). In order to better understand this modest difference, and considering the new information highlighting the role of IBW in tedizolid PK, we performed a post hoc analysis of our previously published data.…”

“…In the ESRD group, infusions were administered either before or within 1 h of completing hemodialysis in a crossover fashion. Detailed methodology and results of this study have been published previously (clinicaltrials.gov registration number NCT01452828) (7). For subjects in the ESRD group, we limited the analysis to PK data obtained when tedizolid was infused postdialysis (although any potential impact of hemodialysis on tedizolid exposure was previously shown to be negligible [7]).…”