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1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models

BACKGROUND: Exebacase (CF-301) is a novel lysin with rapid bacteriolytic and anti-biofilm activity against S. aureus, pronounced synergy with antibiotics and low propensity for resistance. Exebacase has undergone Phase 1–2 trials. This work was to develop pharmacokinetic (PK) model in animal and det...

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Autores principales: Ghahramani, Parviz, Chiu, Joannellyn, Asempa, Tomefa E, Abdelraouf, Kamilia, Nicolau, David P, Abdel Hady, Wessam, Xiong, Yan, Bayer, Arnold, Carabeo, Teresa, Cassino, Cara, Schuch, Raymond, Lehoux, Dario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810366/
http://dx.doi.org/10.1093/ofid/ofz360.1414
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author Ghahramani, Parviz
Chiu, Joannellyn
Asempa, Tomefa E
Abdelraouf, Kamilia
Nicolau, David P
Abdel Hady, Wessam
Xiong, Yan
Bayer, Arnold
Carabeo, Teresa
Cassino, Cara
Schuch, Raymond
Lehoux, Dario
author_facet Ghahramani, Parviz
Chiu, Joannellyn
Asempa, Tomefa E
Abdelraouf, Kamilia
Nicolau, David P
Abdel Hady, Wessam
Xiong, Yan
Bayer, Arnold
Carabeo, Teresa
Cassino, Cara
Schuch, Raymond
Lehoux, Dario
author_sort Ghahramani, Parviz
collection PubMed
description BACKGROUND: Exebacase (CF-301) is a novel lysin with rapid bacteriolytic and anti-biofilm activity against S. aureus, pronounced synergy with antibiotics and low propensity for resistance. Exebacase has undergone Phase 1–2 trials. This work was to develop pharmacokinetic (PK) model in animal and determine the relationship between exebacase exposure and efficacy in animals. METHODS: PK data in 592 animals (4 species) included in population PK model. A range of linear and nonlinear mammillary models with allometric scaling fitted to the PK data using NONMEM and the most parsimonious model was selected by improvement in objective function value (P < 0.01). To evaluate efficacy, 349 animals with 177 mice (neutropenic thigh infection) and 172 rabbits (aortic valve infective endocarditis were treated with exebacase in addition to suboptimal doses of daptomycin (DAP). Full PK profiles were simulated for individual animals. Fifty-nine dosing regimens of exebacase in mice (0–90 mg/kg) and 18 regimens in rabbits (0–1.4 mg/kg) with q24h, q12h and q8h frequencies. Relationship between AUC/MIC, Cmax/MIC, T> MIC, and log-CFU was examined using a range of functions by comparing residual standard error (RSE). RESULTS: 3-compartment model with allometric scaling best described the PK data and was validated by bootstrap and Goodness of Fit. Maximum drop in log(10)CFU/g in target tissues was at AUC/MIC< 0.2 for exebacase when added to DAP that was associated with CF reduction of -5 logs in rabbits (Figure (a)) with similar magnitudes in cardiac vegetations, kidney and spleen, and -4 logs in mice (Figure (b)). Treatment with DAP alone had log(10)CFU reduction of -1 in mice; and -2 in rabbits. AUC/MIC was an appropriate predictor of CFU reductions. CONCLUSION: PK model adequately described the data for 4 animal species. Exebacase addition to DAP has a synergistic effect on efficacy measured by CFU reductions in target tissues in the animal models. Results support previously presented determinations of AUC/MIC as predictor of efficacy. Maximum reductions in CFU in rabbits and mice were observed at AUC/MIC ratios <0.2. These results further indicate that rabbit is the most appropriate efficacy model with MICs and antibacterial activity reflective of previously reported observations in human serum. [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures.
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spelling pubmed-68103662019-10-28 1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models Ghahramani, Parviz Chiu, Joannellyn Asempa, Tomefa E Abdelraouf, Kamilia Nicolau, David P Abdel Hady, Wessam Xiong, Yan Bayer, Arnold Carabeo, Teresa Cassino, Cara Schuch, Raymond Lehoux, Dario Open Forum Infect Dis Abstracts BACKGROUND: Exebacase (CF-301) is a novel lysin with rapid bacteriolytic and anti-biofilm activity against S. aureus, pronounced synergy with antibiotics and low propensity for resistance. Exebacase has undergone Phase 1–2 trials. This work was to develop pharmacokinetic (PK) model in animal and determine the relationship between exebacase exposure and efficacy in animals. METHODS: PK data in 592 animals (4 species) included in population PK model. A range of linear and nonlinear mammillary models with allometric scaling fitted to the PK data using NONMEM and the most parsimonious model was selected by improvement in objective function value (P < 0.01). To evaluate efficacy, 349 animals with 177 mice (neutropenic thigh infection) and 172 rabbits (aortic valve infective endocarditis were treated with exebacase in addition to suboptimal doses of daptomycin (DAP). Full PK profiles were simulated for individual animals. Fifty-nine dosing regimens of exebacase in mice (0–90 mg/kg) and 18 regimens in rabbits (0–1.4 mg/kg) with q24h, q12h and q8h frequencies. Relationship between AUC/MIC, Cmax/MIC, T> MIC, and log-CFU was examined using a range of functions by comparing residual standard error (RSE). RESULTS: 3-compartment model with allometric scaling best described the PK data and was validated by bootstrap and Goodness of Fit. Maximum drop in log(10)CFU/g in target tissues was at AUC/MIC< 0.2 for exebacase when added to DAP that was associated with CF reduction of -5 logs in rabbits (Figure (a)) with similar magnitudes in cardiac vegetations, kidney and spleen, and -4 logs in mice (Figure (b)). Treatment with DAP alone had log(10)CFU reduction of -1 in mice; and -2 in rabbits. AUC/MIC was an appropriate predictor of CFU reductions. CONCLUSION: PK model adequately described the data for 4 animal species. Exebacase addition to DAP has a synergistic effect on efficacy measured by CFU reductions in target tissues in the animal models. Results support previously presented determinations of AUC/MIC as predictor of efficacy. Maximum reductions in CFU in rabbits and mice were observed at AUC/MIC ratios <0.2. These results further indicate that rabbit is the most appropriate efficacy model with MICs and antibacterial activity reflective of previously reported observations in human serum. [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures. Oxford University Press 2019-10-23 /pmc/articles/PMC6810366/ http://dx.doi.org/10.1093/ofid/ofz360.1414 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Ghahramani, Parviz
Chiu, Joannellyn
Asempa, Tomefa E
Abdelraouf, Kamilia
Nicolau, David P
Abdel Hady, Wessam
Xiong, Yan
Bayer, Arnold
Carabeo, Teresa
Cassino, Cara
Schuch, Raymond
Lehoux, Dario
1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
title 1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
title_full 1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
title_fullStr 1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
title_full_unstemmed 1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
title_short 1550. PK-PD Relationship and PK Driver of Efficacy of the Novel Antibacterial Lysin Exebacase (CF-301) in Pre-Clinical Models
title_sort 1550. pk-pd relationship and pk driver of efficacy of the novel antibacterial lysin exebacase (cf-301) in pre-clinical models
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810366/
http://dx.doi.org/10.1093/ofid/ofz360.1414
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