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.

Although many of the effects of opioids are well studied, their activity on the hypogonadal axis is less known. Opioids lead to a decreased level in testosterone by changing the normal excretion of gonadotropins or as a result of changes in the anterior pituitary gland response to these hormones. Long-acting opioids, such as morphine sulfate, methadone, oxycodone and fentanyl, which are used in the treatment of chronic pain, often lead to androgen deficiency induced by opioids (OPIAD-Opioid-Induced Androgen Deficiency). A significant decrease in testosterone levels already occurs during application of 100 to 200 mg of morphine oral formulation. This effect is realized by modifying the normal pulsatile release of the gonadotropins, but also by changing in the response of the anterior pituitary gland up gonadotropin-releasing hormone, which altogether lead to reduced secretion of pituitary hormones, follicle-stimulating hormone and luteinizing hormone. As a result, the reduction in the stimulation of testosterone production in the testes occurs and it leads to hypogonadism. The aim of this review to point out to the occurrence of endocrine disorder caused by chronic use of opioids, as well as to emphasize the need for further research in this area in order to provide a better quality of life for patients with malignant diseases.

Traumatic brain injury is a severe condition frequently complicated with infections, hypermetabolism, and augmented renal clearance (ARC). The ARC is a phenomenon characterized by increased creatinine clearance above 130 mL/min/1.73m2. This phenomenon has been associated with decreased blood concentrations of selected antibiotics, like vancomycin, probably causing treatment failure. Despite ARC's possible fatal consequences in our local medical community, it is rarely assessed. Patient with traumatic brain injury accompanied with secondary infection and augmented renal clearance accompanied with subtherapeutic vancomycin concentrations in the time of treatment is presented. Since concentrations of antibiotics are not routinely measured in Serbian hospitals, clinical practice adjustment and widely accepted method of antibiotics blood concentration measurement which is particularly important in critically ill patients is suggested. The clinical pharmacologist is a significant team member for the treatment of critically ill patients due to his/her expert knowledge of pharmacokinetics and drug interactions, especially important in this category of patients, contributing to positive clinical outcomes.

Background/Aim. Itraconazole (ICZ) is a widely used antifungal drug with hypervariable pharmacokinetics (PK), which is the result of the molecule?s nature itself, as well as the influence of multiple factors. One of the factors is gender, but its importance is not yet substantiated. The aim of the study was to examine the effect of gender on ICZ PK using a two-compartment model, obtained after a single oral dose of the drug, under fed conditions, in healthy participants of both genders. Methods. A previously conducted bioequivalence study of two pharmaceutical formulations of a 100 mg oral dose of ICZ in 38 healthy participants (22 men and 16 women) yielded 114 sets of ICZ plasma concentrations. Of these, 64 sets (40 from men and 24 from women) were analyzed in this study using Kinetica software as they fit the two-compartment model. ICZ plasma concentrations were determined by a previously validated liquid chromatographic method with mass spectrometric detection. Statistical analyses in SPSS included Mann-Whitney U and Fisher?s exact tests for group comparisons, along with Spearman?s correlation for parameter relationships. Results. Poorer ICZ absorption was observed in females compared to males, accompanied by differences in the drug?s distribution process between the central and peripheral compartments and vice versa. What?s more, there are also differences in ICZ elimination between genders, with it being more effective in women. This isn?t solely a result of a more prominent first-pass effect, but is also connected to the terminal phase of elimination after oral administration of the drug. Conclusion. The application of a two-compartment model for ICZ after its single oral dose administration under fed conditions in healthy research participants provided a more detailed insight into the variable PK of this drug, as well as into the existing gender-based differences.

Background: Immune checkpoint inhibitors (ICIs) are effective against melanoma, but are often limited by adverse events (AEs). We aimed to characterise the incidence, characteristics and predictors of AEs. Methods: This ambispective study included 141 patients with melanoma (165 ICI treatment episodes) treated between March 2017 and April 2026. Predictors of AE occurrence, seriousness and severity were analysed per treatment episode and per AE using generalised estimating equations. Results: We recorded 206 AEs in 95 patients (67.4%). At least one AE occurred in 59.8% of pembrolizumab, 59.5% of nivolumab and 81.0% of nivolumab/ipilimumab episodes. Most AEs were Grade 1–2 (88.3%); skin disorders were the most frequent (29.1%) and endocrine AEs had the lowest resolution rate (3.2%). Time to first AE was shortest with nivolumab/ipilimumab (p < 0.001). Per episode, nivolumab/ipilimumab was associated with more serious AEs than nivolumab (p = 0.042) and, borderline, than pembrolizumab (p = 0.051), and with Grade 3–4 AEs (p = 0.001); the lower odds of AE with monotherapy were not significant (p = 0.063, 0.242). Systemic treatment for unresectable disease was associated with AE occurrence (p = 0.029), serious (p = 0.009) and Grade 3–4 AEs (p = 0.016), and BRAF mutation with AE occurrence (p = 0.029). Conclusions: Patients receiving combination immunotherapy and those treated for unresectable disease may warrant closer monitoring.

Background/Objectives: Immunotherapy and targeted therapy improve melanoma survival but raise costs. Real-world cost and outcome data are scarce, especially in Central and Eastern Europe. We estimated per-patient costs and outcomes in Serbia’s public healthcare system. Methods: This retrospective, single-centre study assessed costs in 183 patients with cutaneous melanoma who received systemic therapy at a Serbian tertiary centre (2019–2026). Direct medical costs were reconstructed from invoices and discharge letters from the healthcare-sector perspective. Censoring-adjusted mean 24-month costs were estimated from diagnosis (n = 165) and treatment start (n = 179). Outcomes included overall survival (OS), real-world progression-free survival (rwPFS), and time to next treatment or death (TNT-D). Results: Mean 24-month costs per patient were EUR 66,466 (95% CI 58,465–75,334) from diagnosis (EUR 75,388 with the partitioned estimator), 94.7% for systemic therapy, and EUR 107,229 (95% CI 97,405–118,201) from treatment start. At diagnosis, costs were about twice as high in stages III–IV as in stages I–II. By stage at treatment start, costs were similar in stages III and IV (EUR 102,122 vs. 104,535) despite shorter stage IV survival (p < 0.001). Two-year OS was 91.5% for adjuvant and 51.9% for metastatic first-line intent. Conclusions: Systemic therapy drove costs, which were similar in stages III and IV despite poorer stage IV survival. The cost measurement starting point substantially affected estimates and should be reported.