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

Milijana N Miljković; Nemanja Rančić; Aleksandra Kovačević; Bojana Cikota-Aleksić; Ivan Skadrić; Vesna Jaćević; Momir Mikov; Viktorija Dragojević-Simić

doi:10.3389/fphar.2022.796336

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

Front Pharmacol. 2022 Jun 15:13:796336. doi: 10.3389/fphar.2022.796336. eCollection 2022.

Authors

Milijana N Miljković^{1

2}, Nemanja Rančić^{1

2}, Aleksandra Kovačević^{1

2}, Bojana Cikota-Aleksić^{1

2}, Ivan Skadrić³, Vesna Jaćević^{2

4

5}, Momir Mikov⁶, Viktorija Dragojević-Simić^{1

2}

Affiliations

¹ Centre for Clinical Pharmacology, Military Medical Academy, Belgrade, Serbia.
² Medical Faculty of the Military Medical Academy, University of Defence in Belgrade, Belgrade, Serbia.
³ Institute of Microbiology and Immunology, University of Belgrade, Faculty of Medicine, Belgrade, Serbia.
⁴ Department for Experimental Toxicology and Pharmacology, National Poison Control Centre, Belgrade, Serbia.
⁵ Department for Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czechia.
⁶ Institute for Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.

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 C_max and AUC and increment of V_d 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.

Keywords: age; body mass index; compartmental analysis; gender; genetic polymorphism; hydroxy-itraconazole; itraconazole; non-compartmental analysis.