Safety and Efficacy of Oral and/or Intravenous Tedizolid Phosphate From a Randomized Phase 3 Trial in Adolescents With Acute Bacterial Skin and Skin Structure Infections

Abstract

Background: Tedizolid phosphate is an oxazolidinone prodrug approved in 2014 for treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs); however, efficacy has not previously been evaluated in children. This study compared the safety and efficacy of tedizolid (administered as tedizolid phosphate) with active antibacterial comparators for the treatment of ABSSSIs in adolescents. Methods: This was a randomized, assessor-blind, global phase 3 study of tedizolid versus active comparators for the treatment of Gram-positive ABSSSIs in adolescents (12 to <18 years of age; NCT02276482). Enrolled participants were stratified by region and randomized 3:1 to receive tedizolid phosphate 200 mg (oral and/or intravenous) once daily for 6 days or active comparator, selected by investigator from an allowed list per local standard of care, for 10 days. The primary endpoint was safety; blinded investigator’s assessment of clinical success at the test-of-cure visit (18–25 days after the first dose) was a secondary efficacy endpoint. Statistical comparisons between treatment groups were not performed. Results: Of the 121 participants enrolled, 120 were treated (tedizolid, n = 91; comparator, n = 29). Treatment-emergent adverse events were balanced between treatment groups (tedizolid, 14.3%; comparator, 10.3%). Overall, 3 participants (3.3%) in the tedizolid group and 1 (3.4%) in the comparator group experienced a single drug-related TEAE. Clinical success rates were high in both treatment groups: 96.7% and 93.1% at the test-of-cure visit for the tedizolid and comparator groups, respectively. Conclusions: Tedizolid demonstrated safety and efficacy similar to comparators for the treatment of ABSSSIs in adolescents.

Population Pharmacokinetics, Exposure-Response, and Probability of Target Attainment Analyses for Tedizolid in Adolescent Patients with Acute Bacterial Skin and Skin Structure Infections

“…In PN012, 200 mg of tedizolid phosphate once daily demonstrated an acceptable safety profile. One participant had anemia that was not considered to be drug related; no thrombocytopenia or abnormal neurologic or visual acuity events were observed ( 10 ). Abnormal laboratory values considered potentially clinically significant (PCS) were examined for association with tedizolid exposure.…”

“…The previous popPK model for tedizolid, developed based on adult data and limited adolescent data and derived using well-established modeling methods, was the starting point for the current analysis ( 21 ). The updated model now includes PK data from 16 clinical trials, including the phase 3 PN012 trial in adolescents 12 to <18 years of age ( 10 ) and the phase 1 PN013 trial in children 2 to <12 years of age that was ongoing at the time of the analysis ( 22 ). Only limited adjustments were made to arrive at the current model, as described in the Materials and Methods section, and the updated model displayed good predictive performance for all trials included; thus, no additional covariate screening was conducted.…”

“…At an MIC of 1 μg/ml, PTA was ≥90% for i.v. or orally administered tedizolid ( 10 ). Notably, the S. aureus MIC required to inhibit the growth of 90% of isolates from PN012 and from the Surveillance of Tedizolid Activity and Resistance data that examined approximately 7,800 S. aureus isolates collected in the United States and Europe from 2009 to 2013 were both 0.5 μg/ml ( 5 ).…”

“…Although body weight impacted exposure, no significant dose-response relationship was evident, and no additional safety concerns in the adolescent population were identified. The 200-mg dose in adolescent patients is further supported by the safety and efficacy studies that have been conducted in adult and pediatric participants ( 7 , 8 , 10 ). Therefore, the 200-mg once-daily dose of tedizolid phosphate is appropriate for the treatment of ABSSSIs in adolescent patients.…”

“…Results of the PK analysis showed that the adult dose of 200 mg of tedizolid phosphate was appropriate for further evaluation in this adolescent group. Therefore, the efficacy and safety of 200 mg of tedizolid phosphate were assessed in adolescents with ABSSSIs in a single-blind comparative phase 3 trial ( 10 ). The efficacy of tedizolid phosphate was similar to that of standard-of-care comparators (vancomycin, linezolid, clindamycin, cefazolin, cephalexin, and flucloxacillin), and the safety profile was favorable ( 10 ).…”