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Gómez-López Alicia

Gómez-López Alicia

Mycology Reference and Research Laboratory, Spain

Title: Triazoles Therapeutic Drug Monitoring: From recommendation to applicability

Biography

Biography: Gómez-López Alicia

Abstract

Background: The past three decades have seen a considerable expansion in antifungal drug research that led to the clinical development of antifungal agents with different pharmacologic properties. The new antifungal triazoles (fluconazole FCZ, voriconazole VCZ, itraconazole ICZ, posaconazole PCZ and isavuconazole ISvZ) are widely used for the management of invasive fungal infections (IFI). With the exception of fluconazole, these triazoles exhibit significant inter- and intrapatient pharmacokinetic variability and are associated to multiple drug interactions. Thus, unexpected blood concentrations often need to be evaluated in patients treated with them, to prevent treatment failure or toxicity.  A large number of recent studies suggested that the efficacy and tolerance of azoles can be increased through TDM. Measuring blood concentrations of these antifungals and their metabolites could be used for quick identification of patients with impaired metabolism, a suitable strategy to improve effectiveness of this type of treatment. So, to facilitate dosage adjustment, easy, accurate and precise TDM methods need to be routinely used.

Objective: The aim of the study was to describe systemic azoles pharmacokinetic in a collection of clinical samples using a validated HPLC-PDA assay. The method also allows the simultaneous quantification of triazoles and some of their major metabolites (voriconazole N-oxide VCZ N-oxide, and hidroxy-itraconazole OH-ICZ) in the same run.

Method: The proposed method consists in a simple high-pressure liquid chromatography assay using a stepwise gradient elution profile. It enables the simultaneous quantification of systemic azoles in 150μL of serum samples, after a first step of protein precipitation and direct injection of resulting supernatant. The analytical run enables the specific characterization of azoles by its UV profile. For the validation procedure (following international guidelines) linearity, accuracy and precision parameters were determined. We tested this method by monitoring azole serum concentrations in real clinical samples and using external quality controls. An additional description of the rate metabolite/parent drug is also determined to assess the relevance of metabolites on routinely azole TDM.

Results: The selectivity of the chromatographic procedure and PDA detection allowed good resolution. No significant interfering peaks were detected at similar retention times of the tested compounds. The chromatographic assay took 15 minutes per sample; the retention times were found to be: 7.30 ± 0.3, 9.50 ± 0.3, 11.6 ± 0.3, 11.7 ± 0.3, 12.6± 0.3 and 13.4 ± 0.3 minutes for VCZ N-oxide, VCZ, PCZ, OH-ICZ, ISvZ and ICZ, respectively. The validation procedure establishes that the method was linear between concentrations ranging from 0.25 and 16 mg/L for all components (analytical range). The correlation coefficient was higher than 0.9. Regarding the 115 samples received as part of an international quality control program, we found a high correlation between target and calculated concentration. A high percentage of the remaining clinical samples were received to assess VCZ and Noxide-VCZ (46% and 44% respectively). A great variability in concentration was observed among all the samples evaluated. We also found a high percentage of subtherapeutic samples (sbTh, samples in which azole did not reach the established concentration for efficacy). The mean VCZ Metabolic Rate (MR), established as the ratio between VCZ N-oxide /VCZ for each sample was estimated in 1.7-2, ranging between 0.09 and 25. In the case of ICZ, the mean MR was 1.3-2.   No metabolites have been described for PCZ, so no MR was calculated. Significant MR differences were observed between samples. Higher values were found in sbTh samples compared to those for which upTh concentrations were detected.

Conclusions: This method resulted very simple, fast, cheap and very useful for TDM application, to improve clinical management of antifungal therapy in critically ill patients. According to the results described here, we suggest a role of MR on azole TDM.