Abstract
This study investigated voriconazole (VRC) unbound plasma concentration and its relationship with adverse drug reactions (ADRs) in patients with malignant hematologic disease. Plasma samples were collected from patients or spiked in vitro. A time-saving rapid equilibrium dialysis assay was used for the separation of unbound and bound VRC, following a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis method for drug concentration detection. Liver function and treatment details were collected from the electronic medical records of patients. Protein concentration was determined according to instructions. VRC plasma protein binding rate (PPB) in patient is significantly higher [69.5 ± 6.2%] than that in in-vitro samples, influenced by total drug concentration (Ct), plasma protein concentration, and protein type. The α1-acid glycogen (AAG) has the highest affinity with VRC. Relationship between total PPB of VRC with PPB of individual protein is not a simple addition, but a compressive combination. Unbound drug concentration (Cu) of VRC shows significant relationships with Ct, protein concentration, AST level, metabolism type of CYP2C19 and co-administration of high PPB medicines. Unbound plasma concentration of VRC shows a more sensitive relationship with ADRs than Ct.
Highlights
Voriconazole (VRC), a second generation triazole anti-fungal agent with a spectrum against invasive aspergillosis and Candida albicans infections, has a broader spectrum of activity than traditional triazole agents, and is metabolized mainly by cytochrome P450 2C19 (CYP2C19) (Adwan, 2017)
Voriconazole Unbound Plasma Concentration unbound drug concentration was noticed by clinicians and pharmacists
They investigated the impact of hypoalbuminemia (< 35 g/liter) on VRC pharmacokinetics in adult ICU patients
Summary
Voriconazole (VRC), a second generation triazole anti-fungal agent with a spectrum against invasive aspergillosis and Candida albicans infections, has a broader spectrum of activity than traditional triazole agents (fluconazole and itraconazole), and is metabolized mainly by cytochrome P450 2C19 (CYP2C19) (Adwan, 2017). The plasma binding characteristics of VRC was firstly investigated by Florent et al (2014) in 2013 They found a high correlation between the total concentration (Ct) and unbound concentration (Cu). VRC mainly binded to albumin (25.5 ± 5.1%), and to a lesser extent to a1-acid glycoprotein (AAG; 4.8 ± 1.2%). They investigated the impact of hypoalbuminemia (< 35 g/liter) on VRC pharmacokinetics in adult ICU patients. A positive relationship occurred between voriconazole plasma protein binding rate and plasma albumin concentrations (p < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations (Vanstraelen et al, 2014b)
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