Pharmacokinetics of Tedizolid in Morbidly Obese and Covariate-Matched Nonobese Adults

Abstract

ABSTRACT Tedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of ≥40 kg/m 2 ) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m 2 ) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma ( C max ) and area under the concentration-time curve from 0 h to infinity (AUC 0–∞ ) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different ( P ≥ 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution ( V z ) ( P = 0.110) and clearance (CL) values ( P = 0.214) were comparable between groups. Nearly identical ( P = 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid V z and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC 0–∞ values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.)