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.

Effects of Itraconazole on Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine in Healthy Volunteers

“…Moreover, the compliance of the participants for itraconazole administration can be confirmed by measuring itraconazole and its metabolite (hydroxy-itraconazole) in plasma. 29 Larger volume of distribution (V d /F) of mitragynine than 7OH (521.1 L vs 23.01 L) in this study should be due to the difference in lipophilicity of the compounds. Manda et al have reported the permeability in epithelial cell for mitragynine, which was 1.45−1.50 times higher than that of 7OH.…”

“…29 In females, there was significant reduction of C max and AUC, and increment of V d of itraconazole and hydroxy-itraconazole, compared with males. 29 Given unequal numbers of males and females in our study, i.e., 5 males and 11 females, less exposure to itraconazole in females than in males could occur. This might contribute to the variation for the degree of CYP3A4 inhibition following itraconazole pretreatment.…”

“…Although the other minor metabolic pathways (e.g., CYP2D6 and UGTs) could contribute to the overall metabolism of mitragynine. The influence of gender on itraconazole PK, i.e., AUC and C max , was recently presented . In females, there was significant reduction of C max and AUC, and increment of V d of itraconazole and hydroxy-itraconazole, compared with males .…”

“…Subgroup calculation has shown MR differences in periods 1 and 2 for approximately 6.79 (males) and 3.1 folds (females). Moreover, the compliance of the participants for itraconazole administration can be confirmed by measuring itraconazole and its metabolite (hydroxy-itraconazole) in plasma …”

“…The influence of gender on itraconazole PK, i.e., AUC and C max , was recently presented . In females, there was significant reduction of C max and AUC, and increment of V d of itraconazole and hydroxy-itraconazole, compared with males . Given unequal numbers of males and females in our study, i.e., 5 males and 11 females, less exposure to itraconazole in females than in males could occur.…”