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

Abstract

Tedizolid phosphate is an oxazolidinone antibacterial agent approved for the treatment of Gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate treatment in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to those of the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration-time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the MIC susceptibility breakpoint of 0.5 μg/ml for Staphylococcus and Streptococcus sp. was 100%. As most participants from the PN012 trial were cured, no significant exposure-efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar those in adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.

Keywords: pediatric; pharmacodynamics; pharmacokinetics; skin and soft tissue infections; tedizolid.

FIG 1

Proportion of participants achieving tedizolid fAUC/MIC of ≥3 in the phase 3 PN012 trial in adolescents and global surveillance studies after administration of 200 mg of tedizolid phosphate once daily for 6 days by intravenous (a and b) and oral (c and d) routes. fAUC, area under the concentration-time curve for the free, unbound fraction of a drug; PK/PD, pharmacokinetic/pharmacodynamic.

FIG 2

Distribution of predicted tedizolid AUC_{0–24h_last} (a) and fAUC_{0–24h_last}/MIC (b) in log scale with overall response between cure, failure, and indeterminate at test of cure in the phase 3 PN012 trial in adolescents.^a AUC_{0–24h_last}, area under the concentration-time curve from 0 to 24 hours on the last dosing day; fAUC_{0–24h_last}, area under the concentration-time curve for the free, unbound fraction of the drug from 0 to 24 hours on the last dosing day; MIC, MIC. ^aPharmacokinetic and microbiological data were not available for every participant.

FIG 3

Distribution of tedizolid exposure in adolescents with versus without PCS abnormal hematology values in the phase 3 PN012 trial in adolescents.^a,b. AUC_{0–24h_last}, area under the concentration–time curve from 0 to 24 hours on the last dosing day; C_{max 0–24h_last}, maximum concentration of drug in plasma from 0 to 24 hours on the last dosing day; C_{min 0–24h_last}, minimum concentration of drug in plasma from 0 to 24 hours on the last dosing day; PCS, potentially clinically significant. ^aThe participant with C_max of >9 μg/ml had only one pharmacokinetic data point available to estimate tedizolid exposure. One participant had missing values and could not be evaluated. ^bThe participant with the highest predicted AUC_{0–24h_last} had very high tedizolid plasma concentrations that were mostly excluded as outliers. The AUC_{0–24h_last} for this participant was predicted based on a single concentration measurement after outlier exclusions and should therefore be interpreted with caution.