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Population PK/PD analysis of the bactericidal activity of sutezolid and its major metabolite against intracellular Mtb in whole blood cultures of TB patients Tong Zhu1, Sven Friedrich2, Andreas Diacon2, and Robert Wallis1 1Pfizer, Groton CT; 2Stellenbosch University, Cape Town, South Africa Sutezolid • First oxazolidinone developed for TB • Parent: PNU-100480 or U-480 • Metabolite: PNU-101603 or U-603 • MICs are similar when tested on agar • After oral dosing, plasma concentrations of metabolite are several fold higher than parent • Louie & Drusano found killing of extracellular Mtb in hollow fibers mainly due to the metabolite • Converse & Nuermberger found killing of intracellular Mtb in cell culture models mainly due to the parent Objective • To develop a PK/PD model describing the relative contributions of sutezolid and its metabolite against intracellular Mtb in vivo in patients with pulmonary tuberculosis. Methods • Data (plasma concentrations of U-480 and U-603, and corresponding whole blood bactericidal activity [WBA]) came from patients treated with sutezolid 600 mg BID (N=25) or 1200 mg QD (N=25) enrolled the sutezolid EBA trial (B1171003). • A 4 parameter sigmoid curve was used to describe the concentration-activity relationship, based on prior observations that killing was concentration-dependent at low concentrations, but did not increase further once a maximal response (Imax) was reached. • The activities of U-480 and U-603 were assumed competitive, based on prior observations that U-603 did not further increase the activity of optimal concentrations of U-480. Equations 𝑃+𝑀 𝑊𝐵𝐴 = 𝑊𝐵𝐴0 − 𝐼𝑚𝑎𝑥 ∗ 𝑃+𝑀+1 𝐶480 𝑃 = 0.5 ∗ 𝐼𝐶50 480 𝐶603 𝑀 = 0.5 ∗ 𝐼𝐶50 603 𝛾480 𝛾603 Value the absence of drug Predicted result Fraction of ICfactor Maximal effect Dilution Shapein(Hill) factor 50 Data set • 690 PK and 345 WBA determinations at 0, 1, 2, 3, 6, 8, and 12 hrs post dose measured on days 13-14 • The median ratio of U-603/U-480 plasma concentrations was 7.1 (range, 1 to 28). • High ratios mainly occurred at late time points in the dosing interval. • The wide range of values facilitated modeling of the relative contributions of parent and metabolite. Diagnostic plots Parameters Parameter Fixed effects WBA0 Imax IC50480 ng/mL IC50603 ng/mL g480 g603 Random effects WBA0 (%) Sigma (%) Estimate 0.182 0.597 70.4 1200 2.25 (0.94) 27.4 31.0 90% CI 0.154 to 0.209 0.559 to 0.636 56.0 to 84.9 17x 839 to 2960 1.7 to 3.2 2x 19.4 to 35.2 27.4 to 33.8 Predicted drug activity (in vitro) 0.2 U-603 U-480 log/d 0.0 11x -0.2 -0.4 0.01 0.1 1 Concentration (g/ml) 10 Predicted drug activity (in vivo) Discrete timepoints Cumulative activity BID superior 80% of activity dueQD to to parent Conclusions • Killing of intracellular Mtb by oral sutezolid is mainly due to the parent, despite the higher plasma concentrations reached by the metabolite. • Intracellular drug accumulation may account for this • Mtb subpopulations have distinct roles in TB: • Extracellular: resistance and treatment failure • Intracellular: persistence and relapse • Factors that differentially affect exposure to parent and metabolite (e.g., dosing schedules, induction of metabolism) may have different effects on these 2 outcomes.