title: Tedizolid population pharmacokinetics, exposure response, and target attainment.
abstract: Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0-24)], 7 to 50 μg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 μg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.
authors.affiliation: Cubist, San Diego, California, USA shawn.flanagan@cubist.com.
authors.forename: S
authors.initials: S
authors.lastname: Flanagan
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: J
authors.initials: J
authors.lastname: Passarell
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fiedler-Kelly
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ludwig
authors.affiliation: Cubist, San Diego, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Prokocimer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D005260:Female; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D010755:Organophosphates / Q000009:adverse effects / Q000097:blood; D010080:Oxazoles / Q000009:adverse effects / Q000097:blood; D023303:Oxazolidinones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010976:Platelet Count; D011355:Prodrugs / Q000493:pharmacokinetics; D017192:Skin Diseases, Bacterial / Q000188:drug therapy; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; D011355:Prodrugs; D013777:Tetrazoles; C546016:tedizolid; C515040:tedizolid phosphate