EV0064 ePoster Viewing Antimicrobials: antimicrobial PK/PD, , pharmacoeconomics and general , interaction studies Cross-species plasma binding of tedizolid

M. Varoglu1, L. Nguyen1, H. Shim1, E. Kiim1, S. Flanagan2 1Cubist Pharmaceuticals, Lexington, USA 2Cubist Pharmaceuticals, San Diego, USA

Objectives: Tedizolid phosphate, a novel oxazolidinone antibacterial prodrug, is rapidly converted by endogenous phosphatases to its active moiety tedizolid after administration. Tedizolid has potent activity against a wide range of Gram-positive pathogens and is currently under review by the EMA for treatment of complicated skin and soft tissue infections. Based on clinical data, tedizolid has a favorable pharmacokinetic profile, including high oral , rapid distribution into clinically relevant tissues, long half-life, minimal accumulation, and predictable, linear with low interpatient variability. Plasma protein binding may attenuate the in vivo of a drug, and comparative protein binding data across species are important for conducting preclinical studies. We evaluated plasma protein binding of tedizolid in several studies in humans and non-human species. Methods: In several studies, EDTA-treated pooled plasma samples from mice, rats, rabbits, dogs, monkeys, and male human volunteers were spiked with tedizolid to final concentrations of 0.1 to 50 µg/mL. Protein binding was evaluated by high-throughput dialysis (monkey and rabbit plasma) or ultrafiltration (all others). Protein binding data were also obtained from 5 clinical studies in which plasma samples were spiked with tedizolid ex vivo (predose) or obtained 1, 2, or 12 hours after dosing with tedizolid phosphate (incurred). Results: Plasma protein binding for tedizolid was independent of concentration over the range tested. In spiked EDTA-treated plasma, rank order of protein binding of tedizolid was rat (97.7%) > mouse (92.6%) > human (84.6 %) > rabbit (81.3%) > dog (78.0%) > monkey (69.0%). Protein binding results from clinical studies ranged from 70.0% to 89.4% and were lower for spiked blank samples than for incurred samples (Table). The overall mean protein binding of tedizolid in human plasma samples was 80.3%, calculated based on 1 value per study, using a single average value for studies with duplicate results. Conclusion: Protein binding of tedizolid varied across species from approximately 69% in monkeys to 98% in rats. Binding to human plasma ranged from 70% to approximately 90%. Tedizolid binding was consistently lower in spiked than in incurred samples, possibly because non-specific binding could not be accounted for in incurred samples. StudySample Human Plasma Protein Binding, Mean (SD) 1 Spiked pooled plasma 80.4 (1.5) 2 Spiked pooled plasma 84.6 (2.2) 3 Spiked predose plasma (IV) 70.0 (4.4) 3 Spiked predose plasma (oral) 71.7 (3.7) 4 Spiked predose plasma 73.2 (7.9) 5 Spiked predose plasma 76.4 (4.8) 6 Plasma obtained 1 h after dosing 89.4 (1.6) 7 Plasma obtained 2 h after dosing 87.9 (1.4) 7 Plasma obtained 12 h after dosing 86.6 (2.0)