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Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis

Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal fu...

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Autores principales: Jaber, Mutaz M., Takahashi, Takuto, Kirstein, Mark N., Al‐Kofahi, Mahmoud, Jacobson, Pamala A., Brundage, Richard C.
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/PMC10087276/
https://www.ncbi.nlm.nih.gov/pubmed/36063026
http://dx.doi.org/10.1002/jcph.2144
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author Jaber, Mutaz M.
Takahashi, Takuto
Kirstein, Mark N.
Al‐Kofahi, Mahmoud
Jacobson, Pamala A.
Brundage, Richard C.
author_facet Jaber, Mutaz M.
Takahashi, Takuto
Kirstein, Mark N.
Al‐Kofahi, Mahmoud
Jacobson, Pamala A.
Brundage, Richard C.
author_sort Jaber, Mutaz M.
collection PubMed
description Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed‐effects modeling. Mixed linear and nonlinear elimination pathways were required to adequately describe the disposition of PM. Creatinine clearance (CrCL) was incorporated as a covariate associated with first‐order elimination, representing renal clearance (Cl(R)) of PM. For a 70‐kg patient, Cl(R) was 14.9 L/h, Volume of distribution was 525 L, maximum rate was 81.2 mg/h, and the concentration to achieve 50% of maximum rate was 0.51 mg/L. We conducted simulations to explore the impact of CrCL as a measure of renal function and observed that when CrCL decreases from 120 to 40 mL/min, PM area under the plasma concentration–time curve (AUC) from time 0 to 8 hours and AUC increases by 9.2% and 80.9% on average after a single dose, respectively. Our data suggest that renal function has limited influence on PM exposure during the first 8 hours after dosing but has a large impact on the total exposure. Dose adjustment of cyclophosphamide may not be necessary in hematopoietic cell transplant recipients with moderate to severe kidney dysfunction to attain targeted exposures based on AUC from time 0 to 8 hours. However, dose reduction may be necessary if demonstrated at some future time that total AUC is a better surrogate for safety or toxicity.
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spelling pubmed-100872762023-04-12 Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis Jaber, Mutaz M. Takahashi, Takuto Kirstein, Mark N. Al‐Kofahi, Mahmoud Jacobson, Pamala A. Brundage, Richard C. J Clin Pharmacol Pharmacokinetics Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed‐effects modeling. Mixed linear and nonlinear elimination pathways were required to adequately describe the disposition of PM. Creatinine clearance (CrCL) was incorporated as a covariate associated with first‐order elimination, representing renal clearance (Cl(R)) of PM. For a 70‐kg patient, Cl(R) was 14.9 L/h, Volume of distribution was 525 L, maximum rate was 81.2 mg/h, and the concentration to achieve 50% of maximum rate was 0.51 mg/L. We conducted simulations to explore the impact of CrCL as a measure of renal function and observed that when CrCL decreases from 120 to 40 mL/min, PM area under the plasma concentration–time curve (AUC) from time 0 to 8 hours and AUC increases by 9.2% and 80.9% on average after a single dose, respectively. Our data suggest that renal function has limited influence on PM exposure during the first 8 hours after dosing but has a large impact on the total exposure. Dose adjustment of cyclophosphamide may not be necessary in hematopoietic cell transplant recipients with moderate to severe kidney dysfunction to attain targeted exposures based on AUC from time 0 to 8 hours. However, dose reduction may be necessary if demonstrated at some future time that total AUC is a better surrogate for safety or toxicity. John Wiley and Sons Inc. 2022-09-29 2023-01 /pmc/articles/PMC10087276/ /pubmed/36063026 http://dx.doi.org/10.1002/jcph.2144 Text en © 2022 Genentech Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Pharmacokinetics
Jaber, Mutaz M.
Takahashi, Takuto
Kirstein, Mark N.
Al‐Kofahi, Mahmoud
Jacobson, Pamala A.
Brundage, Richard C.
Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis
title Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis
title_full Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis
title_fullStr Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis
title_full_unstemmed Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis
title_short Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed‐Effects Analysis
title_sort influence of renal function on phosphoramide mustard exposure: a nonlinear mixed‐effects analysis
topic Pharmacokinetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087276/
https://www.ncbi.nlm.nih.gov/pubmed/36063026
http://dx.doi.org/10.1002/jcph.2144
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