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

Abstract

Background: 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, therefore, to describe the total and unbound population pharmacokinetics of intravenous posaconazole in critically ill patients and identify optimal dosing regimens.

Methods: This 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.

Results: From 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.

Conclusions: An 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.

Keywords: Antifungal; Critically ill; Intravenous posaconazole; Unbound pharmacokinetics.

Fig. 1

Schematics of the final structural pharmacokinetic model. C_f(t) and C_b(t) are free and bound posaconazole concentration in the central compartment at time t, respectively. C_p(t), posaconazole concentration in the peripheral compartment at time t; k_e, first-order elimination rate constant; V, volume of distribution of the central compartment; k_cp, rate constant for distribution of unbound posaconazole from central to peripheral compartment; K_pc, rate constant for distribution of unbound posaconazole from peripheral to central compartment; K_on, second-order association rate constant for binding of posaconazole to albumin; K_off, first-order rate constant for dissociation of posaconazole from albumin

Fig. 2

Observed-versus-predicted goodness-of-fit plots for total (top) and unbound (bottom) concentration

Fig. 3

Probability of target attainment for a 300-mg intermittent intravenous infusion (90 min) of posaconazole given every 8 h for simulated patients with fixed BMI of 24 kg/m² and varying albumin level considering total (a) and unbound (b) trough concentration targets

Fig. 4

Probability of target attainment for a 300-mg intermittent intravenous infusion (90 min) of posaconazole given every 8 h for simulated patients with fixed albumin level of 20 g/L and varying BMI values considering total (a) and unbound (b) trough concentration targets