2530. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Ceftobiprole Dose Selection for the Treatment of Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP)
Authors: Bhavnani Sujata M , Hammel Jeffrey P , Rinaldo Anthony J , Smart Jennifer , Litherland Karine , Duncan Leonard R , Jones Mark E , Engelhardt Marc , Ambrose Paul G , Rubino Christopher M 
Published: November 2023

Background

Ceftobiprole medocaril is an intravenously (IV) administered cephalosporin that is rapidly converted in vivo to the active moiety ceftobiprole. Ceftobiprole medocaril is being developed for the treatment of patients with ABSSSI and CABP. PK-PD target attainment analyses were performed to support the dosing regimens selected for these indications.

Methods

Using a population PK model developed for ceftobiprole, PK-PD targets for efficacy, and in vitro surveillance data, percent probabilities of PK-PD target attainment were evaluated among simulated patients with ABSSSI and CABP resembling each clinical trial population. Dosing regimens were adjusted by CLcr group to match exposures among simulated patients with normal renal function administered ceftobiprole 500 mg IV every 8 hours. Randomly assigned ceftobiprole free-drug plasma %T &gt; MIC (%fT &gt;MIC) targets associated with net bacterial stasis and 1- and/or 2-log10 CFU reductions from baseline for S. aureus (SA), Streptococcus species, and Enterobacterales (ENT) based on data from a neutropenic murine-thigh infection model were assessed.

Results

Selected ceftobiprole dosing regimens by CLcr group are shown in Table 1. For ABSSSI, the highest MIC values at which percent probabilities of PK-PD target attainment were ≥ 90% based on randomly assigned %fT &gt; MIC targets associated with net bacterial stasis were ≥ 4 µg/mL for SA and Streptococcus species (inhibiting 100% of isolates) and ≥ 2 µg/mL for ENT (inhibiting 86.5% of isolates) (Table 2). For CABP, the highest MIC values at which percent probabilities of PK-PD target attainment were ≥ 90% based on %fT &gt;MIC targets associated with a 1-log10 CFU reduction from baseline were ≥ 4 µg/mL for S. pneumoniae (inhibiting 100% of isolates) and SA and ≥ 2 µg/mL for ENT (Table 3). Using the same PK-PD target endpoints for each indication, overall percent probabilities of PK-PD target attainment (i.e., averaged over each MIC distribution) were &gt; 99.9% for SA and Streptococcus species or S. pneumoniae and ≥ 98.7% for non-ESBL-producing ENT subsets.

Conclusion

These data provided support for a dosing regimen of ceftobiprole 500 mg IV every 8 hours for patients with ABSSSI or CABP. Dosing regimens should be adjusted for moderate and severe renal impairment including patients with ESRD.

Disclosures

Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: 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|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Jeffrey P. Hammel, MS, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: 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|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: 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, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Anthony J. Rinaldo, B.S., Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: 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|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: 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, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Jennifer Smart, PhD, Basilea Pharmaceutica International Ltd, Allschwil, Switzerland: Stocks/Bonds Karine Litherland, Ph.D., Basilea Pharmaceutica International Ltd, Allschwil, Switzerland: Full time employee|Basilea Pharmaceutica International Ltd, Allschwil, Switzerland: Stocks/Bonds Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mark E. Jones, PhD, Astellas Pharma Global Development, Inc: Support for the present publication|Basilea Pharmaceutica International Ltd: Employee of Basilea Pharmaceutica International Ltd|Basilea Pharmaceutica International Ltd: Stocks/Bonds Marc Engelhardt, MD, Astellas Pharma Global Development, Inc.: Support for the present publication|Basilea Pharmaceutica International Ltd: Employee of Basilea Pharmaceutica International Ltd|Basilea Pharmaceutica International Ltd: Stocks/Bonds Paul G. Ambrose, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: 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|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support Christopher M. Rubino, PharmD, Adagio Therapeutics, Inc.: Grant/Research Support|Albany Medical Center: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: 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|Boston Pharmaceuticals: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Genentech: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|Inotrem: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|Qpex Biopharma: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|Theravance: Grant/Research Support|tranScrip Partners: Grant/Research Support|University of Wisconsin: Grant/Research Support|Utility Therapeutics: Grant/Research Support|ValanBio Therapeutics Inc.: Grant/Research Support|VenatoRx: Grant/Research Support