Population pharmacokinetics of total and unbound concentrations of intravenous posaconazole in adult critically ill patients

Fekade B. Sime,Jason A. Roberts,Therese Starr,Jenie Butler,Janine Stuart,Catherine J. Byrne,Steven C. Wallis,Jeffrey Lipman,Saurabh Pandey,Suzanne Parker

doi:10.1186/s13054-019-2483-9

Abstract

BackgroundThe population pharmacokinetics of total and unbound posaconazole following intravenous administration has not yet been described for the critically ill patient population. The aim of this work was, therefore, to describe the total and unbound population pharmacokinetics of intravenous posaconazole in critically ill patients and identify optimal dosing regimens.MethodsThis was a prospective observational population pharmacokinetic study in critically ill adult patients with presumed/confirmed invasive fungal infection. A single dose of 300 mg posaconazole was administered intravenously as an add-on to standard antifungal therapy, and serial plasma samples were collected over 48 h. Total and unbound posaconazole concentrations, measured by chromatographic method, were used to develop a population pharmacokinetic model and perform dosing simulations in R using Pmetrics.ResultsFrom eight patients, 93 pairs of total and unbound concentrations were measured. A two-compartment linear model with capacity-limited plasma protein binding best described the concentration-time data. Albumin and body mass index (BMI) were included as covariates in the final model. Mean (SD) parameter estimates for the volume of the central compartment (V) and the elimination rate constant were 72 (43) L and 42.1 (23.7) h−1, respectively. Dosing simulations showed that high BMI was associated with a reduced probability of achieving target total and unbound posaconazole concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound posaconazole concentrations.ConclusionsAn important clinical message of this study is that critically ill patients with increased BMI may require larger than approved loading doses of intravenous posaconazole when considering currently recommended dosing targets. Variability in plasma albumin concentration appears unlikely to affect dosing requirements when the assessment is based on unbound concentrations. Where available, therapeutic drug monitoring of unbound concentrations may be useful.

Highlights

The population pharmacokinetics of total and unbound posaconazole following intravenous administration has not yet been described for the critically ill patient population
The product is approved for treatment-refractory cases of invasive fungal infections, which can occur in critically ill patients
The results showed that body mass index (BMI) and serum albumin concentration appear to be important considerations for appropriate dosing of posaconazole

Summary

Introduction

The population pharmacokinetics of total and unbound posaconazole following intravenous administration has not yet been described for the critically ill patient population. The aim of this work was, to describe the total and unbound population pharmacokinetics of intravenous posaconazole in critically ill patients and identify optimal dosing regimens. Posaconazole is a triazole antifungal agent with an extended-spectrum of activity against various yeasts and moulds [1]. It was initially marketed as an oral suspension that exhibited unpredictable pharmacokinetics related to variable bioavailability and later formulated into a sustained-release tablet to improve oral bioavailability [2]. The use of these oral preparations is likely to pose problems in patients with gut dysfunction To avoid these bioavailability problems, an intravenous formulation of posaconazole was recently developed [3]. The lack of pharmacokinetic data derived from critically ill patients means that uncertainty remains on the adequacy of the approved doses for this patient population

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