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Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data
Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top‐down) and th...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381904/ https://www.ncbi.nlm.nih.gov/pubmed/35748042 http://dx.doi.org/10.1002/psp4.12832 |
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author | De Sutter, Pieter‐Jan Van Haeverbeke, Maxime Van Braeckel, Eva Van Biervliet, Stephanie Van Bocxlaer, Jan Vermeulen, An Gasthuys, Elke |
author_facet | De Sutter, Pieter‐Jan Van Haeverbeke, Maxime Van Braeckel, Eva Van Biervliet, Stephanie Van Bocxlaer, Jan Vermeulen, An Gasthuys, Elke |
author_sort | De Sutter, Pieter‐Jan |
collection | PubMed |
description | Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top‐down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom‐up). This was done through meta‐analyses and meta‐regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case‐by‐case basis. |
format | Online Article Text |
id | pubmed-9381904 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93819042022-08-19 Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data De Sutter, Pieter‐Jan Van Haeverbeke, Maxime Van Braeckel, Eva Van Biervliet, Stephanie Van Bocxlaer, Jan Vermeulen, An Gasthuys, Elke CPT Pharmacometrics Syst Pharmacol Reviews Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top‐down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom‐up). This was done through meta‐analyses and meta‐regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case‐by‐case basis. John Wiley and Sons Inc. 2022-06-29 2022-08 /pmc/articles/PMC9381904/ /pubmed/35748042 http://dx.doi.org/10.1002/psp4.12832 Text en © 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Reviews De Sutter, Pieter‐Jan Van Haeverbeke, Maxime Van Braeckel, Eva Van Biervliet, Stephanie Van Bocxlaer, Jan Vermeulen, An Gasthuys, Elke Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data |
title | Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data |
title_full | Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data |
title_fullStr | Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data |
title_full_unstemmed | Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data |
title_short | Altered intravenous drug disposition in people living with cystic fibrosis: A meta‐analysis integrating top‐down and bottom‐up data |
title_sort | altered intravenous drug disposition in people living with cystic fibrosis: a meta‐analysis integrating top‐down and bottom‐up data |
topic | Reviews |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381904/ https://www.ncbi.nlm.nih.gov/pubmed/35748042 http://dx.doi.org/10.1002/psp4.12832 |
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