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1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns
BACKGROUND: Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmaco...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776551/ http://dx.doi.org/10.1093/ofid/ofaa439.1501 |
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author | Hall, Ronald G Pasipanodya, Jotam Putnam, William C Griswold, John Dissanaike, Sharmila Kallem, Raja Reddy Edpuganti, Vindhya Subramaniyan, Indhumathy |
author_facet | Hall, Ronald G Pasipanodya, Jotam Putnam, William C Griswold, John Dissanaike, Sharmila Kallem, Raja Reddy Edpuganti, Vindhya Subramaniyan, Indhumathy |
author_sort | Hall, Ronald G |
collection | PubMed |
description | BACKGROUND: Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. METHODS: A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. RESULTS: The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities [Image: see text] Summary of pharmacokinetic parameters [Image: see text] CONCLUSION: C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. DISCLOSURES: Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support) |
format | Online Article Text |
id | pubmed-7776551 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77765512021-01-07 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns Hall, Ronald G Pasipanodya, Jotam Putnam, William C Griswold, John Dissanaike, Sharmila Kallem, Raja Reddy Edpuganti, Vindhya Subramaniyan, Indhumathy Open Forum Infect Dis Poster Abstracts BACKGROUND: Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. METHODS: A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. RESULTS: The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities [Image: see text] Summary of pharmacokinetic parameters [Image: see text] CONCLUSION: C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. DISCLOSURES: Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support) Oxford University Press 2020-12-31 /pmc/articles/PMC7776551/ http://dx.doi.org/10.1093/ofid/ofaa439.1501 Text en © The Author 2020. 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 | Poster Abstracts Hall, Ronald G Pasipanodya, Jotam Putnam, William C Griswold, John Dissanaike, Sharmila Kallem, Raja Reddy Edpuganti, Vindhya Subramaniyan, Indhumathy 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns |
title | 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns |
title_full | 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns |
title_fullStr | 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns |
title_full_unstemmed | 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns |
title_short | 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns |
title_sort | 1319. pharmacokinetics of ceftolozane/tazobactam in patients with burns |
topic | Poster Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776551/ http://dx.doi.org/10.1093/ofid/ofaa439.1501 |
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