a new hplc validated method for therapeutic monitoring of triazoles in human plasma first results in leukaemic patients

Abstract Therapeutic drug monitoring of triazoles is widely used in clinical practice to optimize therapy, especially in those patients who need antifungal treatment as co-medications. Here it is described development and validation of a new chromatographic method in order to quantify voriconazole and posaconazole in human plasma by ultraviolet detection. After liquid extraction of analytes from plasma using acetonitrile, samples are evaporated to dryness and then reconstituted in mobile phase for chromatographic separation. Analysis is achieved on C18 reverse phase column and eluate is monitored at 250 nm. Mobile phase consisted of 35% water, 15% methanol, 50% acetonitrile. Flavone was used as internal standard; retention times (minutes) were, respectively, for voriconazole 3.9, posaconazole 7.9, flavone 7.1. Accuracy and variability were assayed by inter- and intra-day validation, conducted on three separate days. Methodology was used for the analysis of plasma samples of acute myeloid leukaemia patients in therapy with voriconazole or posaconazole for treatment of fungal infections, in order to perform therapeutic monitoring of antifungal drugs levels. Mean inter- and intra-day accuracy and variability were acceptable for both compounds; thus, method developed resulted linear in the range 0.125–8 μg/mL. Limits of quantification and limits of detection for voriconazole and posaconazole are, respectively, 0.100 and 0.050 μg/mL, and 0.030 and 0.020 μg/mL. It has been observed that voriconazole and posaconazole circulating levels achieved in patients are on average below the therapeutic range defined in literature. In conclusion, method developed and validated in order to quantify voriconazole and posaconazole in human plasma is accurate and precise; it is easily applicable and reproducible, and, therefore, it could be an useful tool in clinical routine to better manage patients in case of multi-therapy approach

Sex Differences on Mitotane Concentration and Treatment Outcome in Patients with Adrenocortical Carcinoma

(1) Background: In clinical settings, data regarding sex are rarely investigated. In women, factors such as body size and composition, hormonal variations, metabolism, and access to care systems and therapy could strongly influence the pharmacological management and the outcome of the therapy. To underline this sex-related difference, we retrospectively collected data from adrenocortical carcinoma patients treated with mitotane, and then evaluated sex-related pharmacokinetics parameters. (2) Methods: A fully validated chromatographic method was used to quantify mitotane concentration in plasma collected from adult patients, also considering the active metabolite ortho,para,dichlorodiphenylethene (o,p′-DDE). Statistical analyses were used to evaluate the sex influence on drugs pharmacokinetics. (3) Results: We found that sex resulted as predictive factor of plasma mitotane and o,p′-DDE concentrations and significantly influenced the attainment of the therapeutic target of mitotane, implying that female sex could be a risk factor of treatment failure. (4) Conclusions: These results suggest that mitotane therapy should be modulated according to patient sex. Furthermore, the proposed approach could contribute to facilitating and disseminating sex-specific pharmacology

Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection

Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure