Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Abstract

f 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.

Factors Impacting Unbound Vancomycin Concentrations in Different Patient Populations

“…Apart from a high PPB, drugs should have affinity for the same albumin binding sites to expel vancomycin from the protein (29). Frequently administered drugs in our study included NSAIDs (PPB, Ͼ90%), aspirin (PPB, Ͼ99%), analgesics (PPB, Ͼ95%), and vitamin K antagonists (PPB, Ͼ90%), drugs known especially for the ability to expel drugs from albumin (17,30). Future studies with vancomycin and albumin and known concentrations of the displacing agents should clarify if the coadministration of highly protein binding drugs has an effect on unbound vancomycin concentrations.…”

Population Pharmacokinetics in China: The Dynamics of Intravenous Voriconazole in Critically Ill Patients with Pulmonary Disease

“…7,8) Moreover, when special treatments were carried out, the pharmacokinetic profile of VRC might display significant variations in critically ill patients, like extracorporeal membrane oxygenation and continuous venous hemofiltration. 4,[9][10][11] Moreover, the different CYP2C19 polymorphism, 12,13) body weight, 14) and life style 15) of Chinese population may result in a varied pharmacokinetic profile of VRC compared to that of westerner's.…”

In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

“…Its high bioavailability (Ն90%) and extensive tissue distribution are advantageous characteristics of voriconazole. On the other hand, voriconazole is also known for exhibiting wide inter-and intraindividual variability in plasma concentrations, depending on an individual's age, liver function, CYP450 polymorphisms, plasma albumin levels, and concomitant medications (4)(5)(6)(7)(8). Furthermore, nonlinear pharmacokinetics complicate the dose-concentration relationship of voriconazole, potentially leading to unpredictable exposures after incremental dose changes (9,10).…”