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Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers

Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total,...

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Autores principales: Yendewa, George A., Griffiss, John McLeod, Gray, Wesley A., Healen, Amanda, Proskin, Howard M., Fulton, Scott A., O’Riordan, Mary Ann, Hoppel, Charles, Blumer, Jeffrey L., Salata, Robert A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029538/
https://www.ncbi.nlm.nih.gov/pubmed/35453240
http://dx.doi.org/10.3390/antibiotics11040490
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author Yendewa, George A.
Griffiss, John McLeod
Gray, Wesley A.
Healen, Amanda
Proskin, Howard M.
Fulton, Scott A.
O’Riordan, Mary Ann
Hoppel, Charles
Blumer, Jeffrey L.
Salata, Robert A.
author_facet Yendewa, George A.
Griffiss, John McLeod
Gray, Wesley A.
Healen, Amanda
Proskin, Howard M.
Fulton, Scott A.
O’Riordan, Mary Ann
Hoppel, Charles
Blumer, Jeffrey L.
Salata, Robert A.
author_sort Yendewa, George A.
collection PubMed
description Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total, 31 healthy adults were enrolled into three cohorts of 9, 10, and 12 participants, respectively. Each cohort received increasing doses of CMS over three dosing periods as follows: Period 1 (IV only), 2.5 mg/kg every 12 h (q12h) to 3.3 mg/kg every 8 h (q8h); Period 2 (aerosolized only), 75 mg 2–4 doses, and Period 3 (combined IV aerosolized), in which was Periods 1 and 2 combined. Safety assessments, serum and lung concentrations of colistin analytes (colistin A, colistin B, CMS A, and CMS B), and kidney biomarkers were measured at specified time points. Increasing the CMS dose from 2.5 mg/kg q12h to q8h resulted in a 33% increase in serum colistin A concentrations from 3.9 μg/mL to 5.3 μg/mL—well above the accepted target of 2 μg/mL for 6 h after dosing, without evidence of nephrotoxicity. However, there was an increase in neurotoxicity, primarily perioral and lingual paresthesias, and self-limited ataxia. IV administration did not increase the lung concentrations of colistin.
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spelling pubmed-90295382022-04-23 Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers Yendewa, George A. Griffiss, John McLeod Gray, Wesley A. Healen, Amanda Proskin, Howard M. Fulton, Scott A. O’Riordan, Mary Ann Hoppel, Charles Blumer, Jeffrey L. Salata, Robert A. Antibiotics (Basel) Article Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total, 31 healthy adults were enrolled into three cohorts of 9, 10, and 12 participants, respectively. Each cohort received increasing doses of CMS over three dosing periods as follows: Period 1 (IV only), 2.5 mg/kg every 12 h (q12h) to 3.3 mg/kg every 8 h (q8h); Period 2 (aerosolized only), 75 mg 2–4 doses, and Period 3 (combined IV aerosolized), in which was Periods 1 and 2 combined. Safety assessments, serum and lung concentrations of colistin analytes (colistin A, colistin B, CMS A, and CMS B), and kidney biomarkers were measured at specified time points. Increasing the CMS dose from 2.5 mg/kg q12h to q8h resulted in a 33% increase in serum colistin A concentrations from 3.9 μg/mL to 5.3 μg/mL—well above the accepted target of 2 μg/mL for 6 h after dosing, without evidence of nephrotoxicity. However, there was an increase in neurotoxicity, primarily perioral and lingual paresthesias, and self-limited ataxia. IV administration did not increase the lung concentrations of colistin. MDPI 2022-04-06 /pmc/articles/PMC9029538/ /pubmed/35453240 http://dx.doi.org/10.3390/antibiotics11040490 Text en © 2022 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 Article
Yendewa, George A.
Griffiss, John McLeod
Gray, Wesley A.
Healen, Amanda
Proskin, Howard M.
Fulton, Scott A.
O’Riordan, Mary Ann
Hoppel, Charles
Blumer, Jeffrey L.
Salata, Robert A.
Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers
title Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers
title_full Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers
title_fullStr Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers
title_full_unstemmed Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers
title_short Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers
title_sort dosing colistimethate every 8 h results in higher plasma concentrations of active colistin than every 12-hourly dosing without increase in nephrotoxicity: a phase 1 pharmacokinetics trial in healthy adult volunteers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029538/
https://www.ncbi.nlm.nih.gov/pubmed/35453240
http://dx.doi.org/10.3390/antibiotics11040490
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