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An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib

Acalabrutinib, commercially known as Calquence(®), is a pharmacological molecule that has robust inhibitory activity against Bruton tyrosine kinase. The medicine in question was carefully developed by the esteemed pharmaceutical company AstraZeneca. The FDA granted authorization on 21 November 2019...

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Autores principales: Attwa, Mohamed W., Bakheit, Ahmed H., Abdelhameed, Ali S., Kadi, Adnan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609012/
https://www.ncbi.nlm.nih.gov/pubmed/37894699
http://dx.doi.org/10.3390/molecules28207220
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author Attwa, Mohamed W.
Bakheit, Ahmed H.
Abdelhameed, Ali S.
Kadi, Adnan A.
author_facet Attwa, Mohamed W.
Bakheit, Ahmed H.
Abdelhameed, Ali S.
Kadi, Adnan A.
author_sort Attwa, Mohamed W.
collection PubMed
description Acalabrutinib, commercially known as Calquence(®), is a pharmacological molecule that has robust inhibitory activity against Bruton tyrosine kinase. The medicine in question was carefully developed by the esteemed pharmaceutical company AstraZeneca. The FDA granted authorization on 21 November 2019 for the utilization of acalabrutinib (ACB) in the treatment of small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) in adult patients. The aim of this study was to develop a UPLC–MS/MS method that is effective, accurate, environmentally sustainable, and has a high degree of sensitivity. The methodology was specifically developed with the intention of quantifying ACB in human liver microsomes (HLMs). The methodology described above was subsequently utilized to assess the metabolic stability of ACB in HLMs in an in vitro environment. The validation procedures for the UPLC–MS/MS method in the HLMs were conducted in accordance with the bioanalytical method validation criteria established by the U.S.- DA. The utilization of the StarDrop software (version 6.6), which integrates the P450 metabolic module and DEREK software (KB 2018 1.1), was employed for the purpose of evaluating the metabolic stability and identifying potential hazardous alarms associated with the chemical structure of ACB. The calibration curve, as established by the ACB, demonstrated a linear correlation across the concentration range of 1 to 3000 ng/mL in the matrix of HLMs. The present study conducted an assessment of the accuracy and precision of the UPLC–MS/MS method in quantifying inter-day and intra-day fluctuations. The inter-day accuracy demonstrated a spectrum of values ranging from −1.00% to 8.36%, whilst the intra-day accuracy presented a range of values spanning from −2.87% to 4.11%. The t(1/2) and intrinsic clearance (Cl(int)) of ACB were determined through in vitro testing to be 20.45 min and 39.65 mL/min/kg, respectively. The analysis concluded that the extraction ratio of ACB demonstrated a moderate level, thus supporting the recommended dosage of ACB (100 mg) to be administered twice daily for the therapeutic treatment of persons suffering from B-cell malignancies. Several computational tools have suggested that introducing minor structural alterations to the butynoyl group, particularly the alpha, beta-unsaturated amide moiety, or substituting this group during the drug design procedure, could potentially enhance the metabolic stability and safety properties of novel derivatives in comparison to ACB.
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spelling pubmed-106090122023-10-28 An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib Attwa, Mohamed W. Bakheit, Ahmed H. Abdelhameed, Ali S. Kadi, Adnan A. Molecules Article Acalabrutinib, commercially known as Calquence(®), is a pharmacological molecule that has robust inhibitory activity against Bruton tyrosine kinase. The medicine in question was carefully developed by the esteemed pharmaceutical company AstraZeneca. The FDA granted authorization on 21 November 2019 for the utilization of acalabrutinib (ACB) in the treatment of small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) in adult patients. The aim of this study was to develop a UPLC–MS/MS method that is effective, accurate, environmentally sustainable, and has a high degree of sensitivity. The methodology was specifically developed with the intention of quantifying ACB in human liver microsomes (HLMs). The methodology described above was subsequently utilized to assess the metabolic stability of ACB in HLMs in an in vitro environment. The validation procedures for the UPLC–MS/MS method in the HLMs were conducted in accordance with the bioanalytical method validation criteria established by the U.S.- DA. The utilization of the StarDrop software (version 6.6), which integrates the P450 metabolic module and DEREK software (KB 2018 1.1), was employed for the purpose of evaluating the metabolic stability and identifying potential hazardous alarms associated with the chemical structure of ACB. The calibration curve, as established by the ACB, demonstrated a linear correlation across the concentration range of 1 to 3000 ng/mL in the matrix of HLMs. The present study conducted an assessment of the accuracy and precision of the UPLC–MS/MS method in quantifying inter-day and intra-day fluctuations. The inter-day accuracy demonstrated a spectrum of values ranging from −1.00% to 8.36%, whilst the intra-day accuracy presented a range of values spanning from −2.87% to 4.11%. The t(1/2) and intrinsic clearance (Cl(int)) of ACB were determined through in vitro testing to be 20.45 min and 39.65 mL/min/kg, respectively. The analysis concluded that the extraction ratio of ACB demonstrated a moderate level, thus supporting the recommended dosage of ACB (100 mg) to be administered twice daily for the therapeutic treatment of persons suffering from B-cell malignancies. Several computational tools have suggested that introducing minor structural alterations to the butynoyl group, particularly the alpha, beta-unsaturated amide moiety, or substituting this group during the drug design procedure, could potentially enhance the metabolic stability and safety properties of novel derivatives in comparison to ACB. MDPI 2023-10-23 /pmc/articles/PMC10609012/ /pubmed/37894699 http://dx.doi.org/10.3390/molecules28207220 Text en © 2023 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
Attwa, Mohamed W.
Bakheit, Ahmed H.
Abdelhameed, Ali S.
Kadi, Adnan A.
An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
title An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
title_full An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
title_fullStr An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
title_full_unstemmed An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
title_short An Ultrafast UPLC–MS/MS Method for Characterizing the In Vitro Metabolic Stability of Acalabrutinib
title_sort ultrafast uplc–ms/ms method for characterizing the in vitro metabolic stability of acalabrutinib
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609012/
https://www.ncbi.nlm.nih.gov/pubmed/37894699
http://dx.doi.org/10.3390/molecules28207220
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