title: Impact of hypoalbuminemia on voriconazole pharmacokinetics in critically ill adult patients.
abstract: Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P = 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.
authors.affiliation: Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University Hospitals Leuven, Leuven, Belgium kim_vanstraelen@hotmail.com.
authors.forename: Kim
authors.initials: K
authors.lastname: Vanstraelen
authors.affiliation: Clinical Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Wauters
authors.affiliation: Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Vercammen
authors.affiliation: Department of Microbiology and Immunology, Laboratory of Nephrology and Renal Transplantation, University Hospitals Leuven/KU Leuven, Leuven, Belgium.
authors.forename: Henriette
authors.initials: H
authors.lastname: de Loor
authors.affiliation: Clinical Department of Haematology, Acute Leukaemia and Stem Cell Transplantation Unit, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.affiliation: Clinical Department of Laboratory Medicine, Department of Microbiology and Immunology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Lagrou
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spriet
mesh_terms: D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism; D002853:Chromatography, Liquid; D016638:Critical Illness; D005260:Female; D006801:Humans; D034141:Hypoalbuminemia / Q000378:metabolism*; D007362:Intensive Care Units; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011485:Protein Binding; D012709:Serum Albumin; D053719:Tandem Mass Spectrometry; D065819:Voriconazole / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D001798:Blood Proteins; D012709:Serum Albumin; D065819:Voriconazole; D001663:Bilirubin