Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection.

Sarah Allegra,Silvia De Francia,Giovanni Di Perri,Antonio D’Avolio,Giovanna Fatiguso,Jessica Cusato,Amedeo De Nicolò,Chiara Carcieri,Elisa Pirro,Fabio Favata

doi:10.3390/biomedicines5040066

Abstract

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.

Highlights

Mortality and morbidity due to invasive fungal infections (IFIs) has increased over the years, despite the development of better and faster diagnostic methods and the availability of antifungal treatments [1]
Azoles remain the corner-stone of prevention and treatment of IFIs, including acute invasive aspergillosis [24]
The clinical use of these drugs is characterized by frequent pharmacological drawbacks in terms of pharmacokinetic variability and drug–drug interactions [25]

Summary

Introduction

Mortality and morbidity due to invasive fungal infections (IFIs) has increased over the years, despite the development of better and faster diagnostic methods and the availability of antifungal treatments [1]. Posaconazole (PSC; Noxafil® ) is a second-generation triazole agent with an extended spectrum of activity. It is used for the treatment of IFIs and is recommended as a first-line prophylaxis during prolonged neutropenia, leukaemia induction treatment and graft-versus-host disease [7]. PSC shows a linear pharmacokinetics with daily doses up to 800 mg; further dose increases do not result in proportional increases in drug exposure [9]. It has poor water solubility, necessitating ingestion with a high-fat meal, and is absorbed at low intestinal pH [10]. The tablet and oral suspension formulations of PSC are not considered interchangeable, due to different dosing and pharmacokinetics [14]

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Methods

Conclusion