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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...

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Autores principales: De Sutter, Pieter‐Jan, Van Haeverbeke, Maxime, Van Braeckel, Eva, Van Biervliet, Stephanie, Van Bocxlaer, Jan, Vermeulen, An, Gasthuys, Elke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
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.
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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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