Pharmacokinetics, tolerability, and safety of TBI-223, a novel oxazolidinone, in healthy participants

ABSTRACT TBI-223 is an oxazolidinone antibiotic under clinical development for the treatment of tuberculosis. Preclinical data indicate potent antituberculosis activity and a potentially improved safety profile over linezolid. In a single-ascending dose study and a multiple-ascending dose study in 114 healthy adults, TBI-223 was generally safe and well tolerated at single doses up to 2,600 mg and multiple doses up to 2,400 mg daily over 14 days. No deaths, serious or severe adverse events, or discontinuations resulting from adverse effects (other than COVID-19) occurred. Except for two instances of orthostatic tachycardia in the single-ascending dose (SAD) study that resolved, no clinically significant electrocardiogram changes were noted. Concentration-QTc modeling found significant relationships of QTc with concentrations of TBI-223 and its main metabolite. However, groups receiving TBI-223 experienced QTc > 450 ms at a similar rate to those receiving placebo. TBI-223 exposures were nearly dose proportional. In the SAD study, TBI-223 exhibited a terminal half-life of 1.9–3.8 hours. Sustained-release tablets achieved a mean AUC 0-inf of 70%–80% relative to immediate-release tablets, with more than 50% lower mean C max . These results support further investigation of TBI-223 for the treatment of tuberculosis. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT03758612 and NCT04865536 .