P-1251. Pharmacometric Analyses to Support Dose Selection of Zoliflodacin, a First-in-Class Oral Antibiotic Being Developed for the Treatment of Uncomplicated Gonorrhea

Abstract Background Zoliflodacin is a first-in-class oral bacterial gyrase inhibitor being developed as single dose treatment for uncomplicated gonorrhea. Population pharmacokinetic (PPK) analyses using data from 6 Phase 1 studies and the pivotal Phase 3 trial and assessments of probabilities of pharmacokinetic-pharmacodynamic (PK-PD) target attainment (PTA) were conducted to support zoliflodacin dose selection. Methods PPK analyses were performed using plasma PK data from 261 participants, including 24 patients from the PK substudy of the pivotal Phase 3 trial. The final, qualified PPK model was used with non-clinical PK-PD and MIC data to perform PTA analyses among fed and fasted simulated patients with Phase 1 and 3 bioavailability estimates. The PK-PD index associated with efficacy is the ratio of free-drug plasma area under the curve from time zero to infinity (AUC0-∞) to MIC, with a target of 70.6 associated with suppression of Neisseria gonorrhoeae mutant amplification [Jacobsson et al., Front Pharmacol. 2021;12:682135]. PTA by MIC and averaged over the MIC distributions for Phase 3 and in vitro surveillance data was assessed among simulated patients. Results A final PPK model with an oral depot compartment and associated relative bioavailability, a transit chain compartment to describe the absorption profile, and one systemic compartment with linear elimination best described the data. Body weight, pre-dose meal type, study phase, sex, formulation type or manufacturer, and concomitant administration of a strong CYP3A4 inhibitor were statistically significant predictors of inter-individual variability in zoliflodacin PK. Age and race were not identified as statistically significant covariates. PTA was ≥ 96.2% at a MIC ≤ 0.25 µg/mL (at which 100 and 99.6% of in vitro surveillance and Phase 3 isolates were inhibited) in simulated patients under fed and fasted conditions, and by bioavailability estimate/study phase (Figure 1). Averaged over either MIC distribution, PTA was ≥ 99.5% under all conditions assessed. Conclusion A PPK model utilizing Phase 1 and 3 data described the zoliflodacin PK well. The high PTA (≥ 96.2 %) at a MIC ≤ 0.25 µg/mL and over the MIC distributions supported a 3 g single oral dose of zoliflodacin for the treatment of uncomplicated gonorrhea. Disclosures Sujata M. Bhavnani, PharmD; MS; FIDSA, Achaogen Inc.: Grant/Research Support|Adagio Therapeutics, Inc.: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics, LLC.: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Cumberland Pharmaceuticals Inc.: Grant/Research Support|Entasis Therapeutics Inc., an affiliate of Innoviva Specialty Therapeutics, Inc.: Grant/Research Support|Excalibur Pharmaceuticals Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genetech: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Global Antibiotic Research and Development Partnership: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Inoterm: Grant/Research Support|Insmed Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Ownership Interest|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100 Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi Inc.: Advisor/Consultant|Shionogi Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences Inc.: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|University of Wisconsin: Grant/Research Support|US Food and Drug Administration: Grant/Research Support|UT Southwestern: Grant/Research Support|ValanBio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Zogenix International: Grant/Research Support Anthony P. Cammarata, M.S., Achaogen Inc.: Grant/Research Support|Adagio Therapeutics, Inc.: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics, LLC.: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Cumberland Pharmaceuticals Inc.: Grant/Research Support|Entasis Therapeutics Inc., an affiliate of Innoviva Specialty Therapeutics, Inc.: Grant/Research Support|Excalibur Pharmaceuticals Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genetech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Global Antibiotic Research and Development Partnership: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100 Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Shionogi Inc.: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Spruce Biosciences Inc.: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|University of Wisconsin: Grant/Research Support|US Food and Drug Administration: Grant/Research Support|UT Southwestern: Grant/Research Support|ValanBio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Zogenix International: Grant/Research Support Jeffrey P. Hammel, MS, Achaogen Inc.: Grant/Research Support|Adagio Therapeutics, Inc.: Grant/Research Support|AiCuris Anti-infective Cures AG: Grant/Research Support|Albany Medical College: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Apogee Biologics, Inc.: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|BioFire Diagnostics, LLC.: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Cumberland Pharmaceuticals Inc.: Grant/Research Support|Entasis Therapeutics Inc., an affiliate of Innoviva Specialty Therapeutics, Inc.: Grant/Research Support|Excalibur Pharmaceuticals Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genetech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Global Antibiotic Research and Development Partnership: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Institute for Clinical Pharmacodynamics, Inc.: Employee|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience: Grant/Research Support|Lassen Therapeutics Inc.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novobiotic Pharmaceuticals LLC.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Pfizer Inc.: Grant/Research Support|Praxis Precision Medicines, Inc.: Grant/Research Support|PTC Therapeutics: Grant/Research Support|PureTech LYT 100 Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Renibus Therapeutics: Grant/Research Support|Sfunga Therapeutics: Grant/Research