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Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses

Antibiotic efficacy determination in clinical trials often relies on non-inferiority designs because they afford smaller study sample sizes. These efficacy studies tend to exclude patients within specific populations or include too few patients to discern potential differences in their clinical outc...

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Detalles Bibliográficos
Autores principales: Pai, Manjunath P., Crass, Ryan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614818/
https://www.ncbi.nlm.nih.gov/pubmed/34827306
http://dx.doi.org/10.3390/antibiotics10111368
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author Pai, Manjunath P.
Crass, Ryan L.
author_facet Pai, Manjunath P.
Crass, Ryan L.
author_sort Pai, Manjunath P.
collection PubMed
description Antibiotic efficacy determination in clinical trials often relies on non-inferiority designs because they afford smaller study sample sizes. These efficacy studies tend to exclude patients within specific populations or include too few patients to discern potential differences in their clinical outcomes. As a result, dosing guidance in patients with abnormal liver and kidney function, age across the lifespan, and other specific populations relies on drug exposure-matching. The underlying assumption for exposure-matching is that the disease course and the response to the antibiotic are similar in patients with and without the specific condition. While this may not be the case, clinical efficacy studies are underpowered to ensure this is true. The current paper provides an integrative review of the current approach to dose selection in specific populations. We review existing clinical trial endpoints that could be measured on a more continuous rather than a discrete scale to better inform exposure–response relationships. The inclusion of newer systemic biomarkers of efficacy can help overcome the current limitations. We use a modeling and simulation exercise to illustrate how an efficacy biomarker can inform dose selection better. Studies that inform response-matching rather than exposure-matching only are needed to improve dose selection in specific populations.
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spelling pubmed-86148182021-11-26 Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses Pai, Manjunath P. Crass, Ryan L. Antibiotics (Basel) Review Antibiotic efficacy determination in clinical trials often relies on non-inferiority designs because they afford smaller study sample sizes. These efficacy studies tend to exclude patients within specific populations or include too few patients to discern potential differences in their clinical outcomes. As a result, dosing guidance in patients with abnormal liver and kidney function, age across the lifespan, and other specific populations relies on drug exposure-matching. The underlying assumption for exposure-matching is that the disease course and the response to the antibiotic are similar in patients with and without the specific condition. While this may not be the case, clinical efficacy studies are underpowered to ensure this is true. The current paper provides an integrative review of the current approach to dose selection in specific populations. We review existing clinical trial endpoints that could be measured on a more continuous rather than a discrete scale to better inform exposure–response relationships. The inclusion of newer systemic biomarkers of efficacy can help overcome the current limitations. We use a modeling and simulation exercise to illustrate how an efficacy biomarker can inform dose selection better. Studies that inform response-matching rather than exposure-matching only are needed to improve dose selection in specific populations. MDPI 2021-11-09 /pmc/articles/PMC8614818/ /pubmed/34827306 http://dx.doi.org/10.3390/antibiotics10111368 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Pai, Manjunath P.
Crass, Ryan L.
Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses
title Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses
title_full Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses
title_fullStr Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses
title_full_unstemmed Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses
title_short Translation of Pharmacodynamic Biomarkers of Antibiotic Efficacy in Specific Populations to Optimize Doses
title_sort translation of pharmacodynamic biomarkers of antibiotic efficacy in specific populations to optimize doses
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614818/
https://www.ncbi.nlm.nih.gov/pubmed/34827306
http://dx.doi.org/10.3390/antibiotics10111368
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