P-1229. Assessment of Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment for the Anti-Staphylococcal Antibiotic Afabicin
Authors: Cameron David , Dao Justine , Rubino Christopher M , Menetrey Annick , Cammarata Anthony P , Hammel Jeffrey P , Dieppois Guennaelle , Nowakowska Justyna , Bravo Juan , VanScoy Brian D , Hawser Stephen , Nicolas-Metral Valerie , Bhavnani Sujata M 
Published: January 2025

Background

Afabicin is a novel antimicrobial in clinical development for the treatment of staphylococcal infections. Its active moiety, afabicin desphosphono (Debio 1452), inhibits the essential enoyl-ACP reductase enzyme FabI, exerting antimicrobial effects by disrupting fatty acid biosynthesis. Herein, we describe an assessment of the probability of PK-PD target attainment (PTA) to support afabicin dose selection for patients with bone and joint infections (BJI).

Methods

MICs for 872 Staphylococcus aureus clinical isolates collected from 2017 to 2023 were determined according to CLSI guidelines (M07). Afabicin desphosphono plasma PK parameters from S. aureus infected mice were determined by non-compartmental analysis. Efficacy data for S. aureus (ATCC 33591, MIC = 0.015 µg/ml) were collected from a dose-ranging study conducted in an immunocompetent thigh infection model. The relationship between change in log10CFU from baseline and free-drug plasma AUC (fAUC):MIC ratio was evaluated by fitting a Hill-type model. A population PK model was developed using data from Phase 1 and an ongoing Phase 2 study in BJI. Monte Carlo simulations were used to generate fAUC in simulated patients in a partially fed state after administration of afabicin 55 mg IV BID on day 1 followed by 80 mg PO BID starting on day 2. PTA by MIC, and averaged over the MIC distribution was assessed on days 1 and 2.

Results

Afabicin desphosphono displayed potent in vitro activity against S. aureus in vitro with a MIC90 of 0.015 µg/ml (range 0.002 – 0.25 µg/ml). MICs were similar for MSSA and MRSA. A Hill-type model described the PK-PD relationship in immunocompetent mice well. Based on this model, the derived fAUC:MIC ratio targets associated with net bacterial stasis, 1- and 2-log10CFU reductions were 2.2, 3.4, and 8.4, respectively. PTA on days 1 and 2 for the evaluated dosing regimen was ≥ 99.3% at the MIC90, and ≥ 92.7% averaged over the MIC distribution for S. aureus for all three targets (Figure 1).

Conclusion

These data support the afabicin dosing regiment of 55 mg IV BID / 80 mg PO for the treatment of patients with S. aureus infections, which is further substantiated by clinical observations from an ongoing Phase 2 study in BJI (NCT03723551)

Disclosures

David Cameron, PhD, Debiopharm International S.A.: Salary Justine Dao, n/a, Debiopharm International: Salary Christopher M. Rubino, PharmD, 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|Genentech: 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.: 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.: 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 Annick Menetrey, n/a, Debiopharm International: Salary 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 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 Guennaelle Dieppois, n/a, Debiopharm International: Salary Justyna Nowakowska, n/a, Debiopharm International: Salary Juan Bravo, n/a, Debiopharm International: Salary Brian D. VanScoy, B.S., Achaogen Inc.: Grant/Research Support|Adagio Therapeutics, Inc.: Grant/Research Support|AiCurtis 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: Grant/Research Support|Excalibur Pharmaceuticals Inc.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Global Antibiotic Research and Development Partnership: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Employee|Inotrem: Grant/Research Support|Insmed Inc: Grant/Research Support|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 Valerie Nicolas-Metral, PhD, Debiopharm International: Salary 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