Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis

Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Milijana N. Miljković [verfasserIn] Nemanja Rančić [verfasserIn] Aleksandra Kovačević [verfasserIn] Bojana Cikota-Aleksić [verfasserIn] Ivan Skadrić [verfasserIn] Vesna Jaćević [verfasserIn] Momir Mikov [verfasserIn] Viktorija Dragojević-Simić [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism

Übergeordnetes Werk:	In: Frontiers in Pharmacology - Frontiers Media S.A., 2010, 13(2022)
Übergeordnetes Werk:	volume:13 ; year:2022

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fphar.2022.796336

Katalog-ID:	DOAJ04244389X

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allfields	10.3389/fphar.2022.796336 doi (DE-627)DOAJ04244389X (DE-599)DOAJe50802fedeb94db580c520ca759170a1 DE-627 ger DE-627 rakwb eng RM1-950 Milijana N. Miljković verfasserin aut Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite. itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism Therapeutics. Pharmacology Milijana N. Miljković verfasserin aut Nemanja Rančić verfasserin aut Nemanja Rančić verfasserin aut Aleksandra Kovačević verfasserin aut Aleksandra Kovačević verfasserin aut Bojana Cikota-Aleksić verfasserin aut Bojana Cikota-Aleksić verfasserin aut Ivan Skadrić verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Momir Mikov verfasserin aut Viktorija Dragojević-Simić verfasserin aut Viktorija Dragojević-Simić verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 13(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:13 year:2022 https://doi.org/10.3389/fphar.2022.796336 kostenfrei https://doaj.org/article/e50802fedeb94db580c520ca759170a1 kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2022.796336/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
spelling	10.3389/fphar.2022.796336 doi (DE-627)DOAJ04244389X (DE-599)DOAJe50802fedeb94db580c520ca759170a1 DE-627 ger DE-627 rakwb eng RM1-950 Milijana N. Miljković verfasserin aut Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite. itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism Therapeutics. Pharmacology Milijana N. Miljković verfasserin aut Nemanja Rančić verfasserin aut Nemanja Rančić verfasserin aut Aleksandra Kovačević verfasserin aut Aleksandra Kovačević verfasserin aut Bojana Cikota-Aleksić verfasserin aut Bojana Cikota-Aleksić verfasserin aut Ivan Skadrić verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Momir Mikov verfasserin aut Viktorija Dragojević-Simić verfasserin aut Viktorija Dragojević-Simić verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 13(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:13 year:2022 https://doi.org/10.3389/fphar.2022.796336 kostenfrei https://doaj.org/article/e50802fedeb94db580c520ca759170a1 kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2022.796336/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
allfields_unstemmed	10.3389/fphar.2022.796336 doi (DE-627)DOAJ04244389X (DE-599)DOAJe50802fedeb94db580c520ca759170a1 DE-627 ger DE-627 rakwb eng RM1-950 Milijana N. Miljković verfasserin aut Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite. itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism Therapeutics. Pharmacology Milijana N. Miljković verfasserin aut Nemanja Rančić verfasserin aut Nemanja Rančić verfasserin aut Aleksandra Kovačević verfasserin aut Aleksandra Kovačević verfasserin aut Bojana Cikota-Aleksić verfasserin aut Bojana Cikota-Aleksić verfasserin aut Ivan Skadrić verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Momir Mikov verfasserin aut Viktorija Dragojević-Simić verfasserin aut Viktorija Dragojević-Simić verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 13(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:13 year:2022 https://doi.org/10.3389/fphar.2022.796336 kostenfrei https://doaj.org/article/e50802fedeb94db580c520ca759170a1 kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2022.796336/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
allfieldsGer	10.3389/fphar.2022.796336 doi (DE-627)DOAJ04244389X (DE-599)DOAJe50802fedeb94db580c520ca759170a1 DE-627 ger DE-627 rakwb eng RM1-950 Milijana N. Miljković verfasserin aut Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite. itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism Therapeutics. Pharmacology Milijana N. Miljković verfasserin aut Nemanja Rančić verfasserin aut Nemanja Rančić verfasserin aut Aleksandra Kovačević verfasserin aut Aleksandra Kovačević verfasserin aut Bojana Cikota-Aleksić verfasserin aut Bojana Cikota-Aleksić verfasserin aut Ivan Skadrić verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Momir Mikov verfasserin aut Viktorija Dragojević-Simić verfasserin aut Viktorija Dragojević-Simić verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 13(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:13 year:2022 https://doi.org/10.3389/fphar.2022.796336 kostenfrei https://doaj.org/article/e50802fedeb94db580c520ca759170a1 kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2022.796336/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
allfieldsSound	10.3389/fphar.2022.796336 doi (DE-627)DOAJ04244389X (DE-599)DOAJe50802fedeb94db580c520ca759170a1 DE-627 ger DE-627 rakwb eng RM1-950 Milijana N. Miljković verfasserin aut Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite. itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism Therapeutics. Pharmacology Milijana N. Miljković verfasserin aut Nemanja Rančić verfasserin aut Nemanja Rančić verfasserin aut Aleksandra Kovačević verfasserin aut Aleksandra Kovačević verfasserin aut Bojana Cikota-Aleksić verfasserin aut Bojana Cikota-Aleksić verfasserin aut Ivan Skadrić verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Vesna Jaćević verfasserin aut Momir Mikov verfasserin aut Viktorija Dragojević-Simić verfasserin aut Viktorija Dragojević-Simić verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 13(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:13 year:2022 https://doi.org/10.3389/fphar.2022.796336 kostenfrei https://doaj.org/article/e50802fedeb94db580c520ca759170a1 kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2022.796336/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022
language	English
source	In Frontiers in Pharmacology 13(2022) volume:13 year:2022
sourceStr	In Frontiers in Pharmacology 13(2022) volume:13 year:2022
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism Therapeutics. Pharmacology
isfreeaccess_bool	true
container_title	Frontiers in Pharmacology
authorswithroles_txt_mv	Milijana N. Miljković @@aut@@ Nemanja Rančić @@aut@@ Aleksandra Kovačević @@aut@@ Bojana Cikota-Aleksić @@aut@@ Ivan Skadrić @@aut@@ Vesna Jaćević @@aut@@ Momir Mikov @@aut@@ Viktorija Dragojević-Simić @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	642889392
id	DOAJ04244389X
language_de	englisch
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callnumber-first	R - Medicine
author	Milijana N. Miljković
spellingShingle	Milijana N. Miljković misc RM1-950 misc itraconazole misc hydroxy-itraconazole misc gender misc non-compartmental analysis misc compartmental analysis misc genetic polymorphism misc Therapeutics. Pharmacology Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis
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topic_title	RM1-950 Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis itraconazole hydroxy-itraconazole gender non-compartmental analysis compartmental analysis genetic polymorphism
topic	misc RM1-950 misc itraconazole misc hydroxy-itraconazole misc gender misc non-compartmental analysis misc compartmental analysis misc genetic polymorphism misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc itraconazole misc hydroxy-itraconazole misc gender misc non-compartmental analysis misc compartmental analysis misc genetic polymorphism misc Therapeutics. Pharmacology
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title	Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis
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title_full	Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis
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author_browse	Milijana N. Miljković Nemanja Rančić Aleksandra Kovačević Bojana Cikota-Aleksić Ivan Skadrić Vesna Jaćević Momir Mikov Viktorija Dragojević-Simić
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title_sort	influence of gender, body mass index, and age on the pharmacokinetics of itraconazole in healthy subjects: non-compartmental versus compartmental analysis
callnumber	RM1-950
title_auth	Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis
abstract	Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.
abstractGer	Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.
abstract_unstemmed	Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.
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title_short	Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis
url	https://doi.org/10.3389/fphar.2022.796336 https://doaj.org/article/e50802fedeb94db580c520ca759170a1 https://www.frontiersin.org/articles/10.3389/fphar.2022.796336/full https://doaj.org/toc/1663-9812
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Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis

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