Tedizolid population pharmacokinetics, exposure response, and target attainment

• Published in: Antimicrobial agents and chemotherapy 2014-11, Vol.58 (11), p.6462-6470
• Main Authors: Flanagan, S, Passarell, J, Lu, Q, Fiedler-Kelly, J, Ludwig, E, Prokocimer, P
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anti-Bacterial Agents; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - blood; Anti-Bacterial Agents - pharmacokinetics; Area Under Curve; Biological Availability; Comment On; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Middle Aged; Neutrophils - drug effects; Organophosphates - adverse effects; Organophosphates - blood; Oxazoles - adverse effects; Oxazoles - blood; Oxazolidinones; Oxazolidinones - adverse effects; Oxazolidinones - blood; Oxazolidinones - pharmacokinetics; Pharmacology; Platelet Count; Prodrugs - pharmacokinetics; Skin Diseases, Bacterial - drug therapy; Staphylococcal Infections; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Tetrazoles; Tetrazoles - adverse effects; Tetrazoles - blood; Tetrazoles - pharmacokinetics; Young Adult
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.03423-14

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.