Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

Fekade B Sime; Janine Stuart; Jenie Butler; Therese Starr; Steven C Wallis; Saurabh Pandey; Jeffrey Lipman; Jason A Roberts

doi:10.1128/AAC.00242-18

Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

Antimicrob Agents Chemother. 2018 May 25;62(6):e00242-18. doi: 10.1128/AAC.00242-18. Print 2018 Jun.

Authors

Fekade B Sime¹, Janine Stuart², Jenie Butler², Therese Starr², Steven C Wallis³, Saurabh Pandey³, Jeffrey Lipman^{2

3}, Jason A Roberts^{4

2

3

5}

Affiliations

¹ School of Pharmacy, Centre for Translational Anti-Infective Pharmacodynamics, The University of Queensland, Brisbane, Australia.
² Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.
³ University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
⁴ School of Pharmacy, Centre for Translational Anti-Infective Pharmacodynamics, The University of Queensland, Brisbane, Australia j.roberts2@uq.edu.au.
⁵ Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Abstract

To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period (C_max), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC_0-∞), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution (V), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC_0-∞ was 39% of the values reported for heathy volunteers. The AUC_0-∞ was only 52% of the steady-state AUC_0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in this cohort of critically ill patients compared to those in healthy volunteers and hematology patients.

Keywords: antifungal; dosing; intensive care unit; pharmacodynamics; triazole antifungal.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intravenous
Adult
Antifungal Agents / administration & dosage*
Antifungal Agents / pharmacokinetics*
Critical Illness
Female
Humans
Intensive Care Units
Male
Middle Aged
Prospective Studies
Triazoles / administration & dosage*
Triazoles / pharmacokinetics*

Substances

Antifungal Agents
Triazoles
posaconazole