Development and Validation of Voriconazole Concentration by LC‐MS‐MS: Applied in Clinical Implementation

Prommas, Santirhat; Puangpetch, Apichaya; Jenjirattithigarn, Nuttawut; Chuwongwattana, Sumonrat; Jantararoungtong, Thawinee; Koomdee, Napatrupron; Santon, Siwalee; Chamnanphon, Montri; Sukasem, Chonlaphat

doi:10.1002/jcla.22011

Cited by 14 publications

(4 citation statements)

References 24 publications

(40 reference statements)

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“…Voriconazole trough plasma concentrations were determined using validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). 18 All intra-and interday accuracy (%) and precision (%CV) measurements were within acceptable ranges recommended by the US-FDA guidelines for bioanalytical method validation. 19 The lower limit of quantification (LLOQ) for voriconazole was 0.05 µg/mL.…”

Section: Blood Sampling and Analytical Assaysmentioning

confidence: 64%

“…Blood samples were taken in steady‐state one hour before voriconazole administration. Voriconazole trough plasma concentrations were determined using validated high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) 18 . All intra‐ and interday accuracy (%) and precision (%CV) measurements were within acceptable ranges recommended by the US‐FDA guidelines for bioanalytical method validation 19 .…”

Section: Methodsmentioning

confidence: 99%

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Impact ofCYP2C19,CYP3A4,ABCB1, andFMO3genotypes on plasma voriconazole in Thai patients with invasive fungal infections

Chuwongwattana

Jantararoungtong

Prommas

et al. 2020

Pharmacology Res & Perspec

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Voriconazole is the first‐line antifungal choice in the treatment of invasive fungal infections (IFIs). Single nucleotide polymorphisms (SNPs) in drug‐metabolizing and transporter genes may affect voriconazole pharmacokinetics. This study aimed to determine the frequency of the CYP2C19 rs4244285, rs4986893, rs72552267, and rs12248560, CYP3A4 rs4646437, ABCB1 rs1045642, and FMO3 rs2266782 alleles and determine the association between these genetic variants and voriconazole concentrations in Thai patients with invasive fungal infections. The study comprised 177 Thai patients with IFIs in whom seven SNPs in CYP2C19 , CYP3A4 , ABCB1, and FMO3 were genotyped using Taq Man real‐time polymerase chain reaction (RT‐PCR) 5´ nuclease assays, and voriconazole plasma concentrations were measured by high‐performance liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Of the 177 patients included, 31 were <12 years and 146 were ≥12 years. The CYP2C19 allele frequencies were 0.29 for *2 , 0.060 for *3 , 0.003 for *6 , and 0.008 for *17 . The allele frequency of CYP3A4 (rs4646437) was 0.26, ABCB1 (rs1045642) was 0.36, and FMO3 (rs2266782) was 0.16. The median voriconazole dose/weight was significantly lower in patients aged ≥12 years when compared to the patients aged <12 years ( P < .001). Patients aged <12 years with CYP2C19*1/*2 exhibited significantly higher median voriconazole plasma concentrations than those with the CYP2C19*1/*1 ( P = .038). However, there were no significant differences in median voriconazole plasma concentrations among the CYP2C19 genotypes in the patients aged ≥12 years. There was a lack of association observed among the CYP3A4, ABCB1, and FMO3 genotypes on the plasma voriconazole concentrations in both groups of patients. Our findings indicate that voriconazole plasma concentrations are affected by the CYP2C19*2 allele in patients aged <12 years but not in patients aged ≥12 years.

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Section: Blood Sampling and Analytical Assaysmentioning

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Impact ofCYP2C19,CYP3A4,ABCB1, andFMO3genotypes on plasma voriconazole in Thai patients with invasive fungal infections

Chuwongwattana

Jantararoungtong

Prommas

et al. 2020

Pharmacology Res & Perspec

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“…According to the United States Food and Drug Administration bioanalytical method validation guidance (U.S. Food and Drug Administration, 2001), this method is fully validated for specificity, linearity, precision, accuracy, recovery, matrix effect, and stability. In some previously developed LC-MS/MS methods (Al-Ghobashy et al, 2018;Prommas et al, 2017), fluconazole was used as the internal standard. Considering that VRC might be used after fluconazole in clinical settings, we used deuterated VRC (D3-voriconazole) as the internal standard, which eliminated the interference of drugs including fluconazole on the detection of the internal standard.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit

Lin

Huang

et al. 2020

International Journal of Infectious Diseases

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To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. Methods: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. Results: There were good correlations between the area under the curve (AUC 0-12 ) of PK curve 2 and the corresponding trough concentration (C 0 ) and peak concentration (C max ) (r 2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t 1/2 ) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (V ss ) of PK curve 1 was positively correlated with actual body weight (r 2 = 0.450, p = 0.004). The median first C 0 of 17 patients determined on day 5 was 5.27 (2.61) mg/ml, and 29.4% of C 0 exceeded the upper limit of the therapeutic window (2-6 mg/ml). Conclusions:The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t 1/2 , which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.

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“…It is a simple and rapid method for monitoring triazole antifungals but is not easily accessible [19]. Prommas et al used LC-MS-MS with fast and accurate runtime, but it is costly and not available in all laboratories [20].…”

Section: Discussionmentioning

confidence: 99%

Determination of Voriconazole Plasma Concentration by HPLC Technique and Evaluating Its Association with Clinical Outcome and Adverse Effects in Patients with Invasive Aspergillosis

Yousefian

Dastan

Marjani

et al. 2021

Canadian Journal of Infectious Diseases and Medical Microbiolog

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Purpose. Invasive aspergillosis is a prevalent fungal disease, especially in Asian countries with a high mortality rate. Voriconazole (VRZ) is the first choice for invasive aspergillosis treatment. Plasma concentration of this drug is unpredictable and varies among individuals. This variability is influenced by many factors leading to clinical implication. Therapeutic drug monitoring (TDM) may have a crucial role in the patients’ treatment process. The HPLC method provides sufficient specificity and sensitivity for plasma VRZ concentration determination for TDM purposes of this drug. Methods. Patients who initiated oral or intravenous VRZ for invasive aspergillosis were enrolled in this study. Demographic characteristics and clinical data, outcome, and adverse effects were documented. For each patient, the plasma sample was collected under steady-state condition and analyzed using a validated HPLC method. Results. A total of 22 measurements were performed. Fifty percent of patients were out of the therapeutic range. From them, 27.27% and 22.73% were in subtherapeutic and supratherapeutic ranges (<1 μg/mL and >5.5 μg/mL), respectively. There was a significant correlation between VRZ plasma concentration and treatment outcomes ( P = 0.022 ). Treatment failure was five times higher than treatment success in those in the subtherapeutic range. Adverse effects were observed more frequently in patients with supratherapeutic concentrations compared to those with non-supratherapeutic levels. Furthermore, the mortality rate in patients experiencing treatment failure was 2.17 times higher than those with treatment success. Conclusions. TDM of VRZ plays an important role in better evaluation of efficacy and toxicity during treatment. Therefore, determination of the drug level may be of clinical significance.

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Development and Validation of Voriconazole Concentration by LC‐MS‐MS: Applied in Clinical Implementation

Abstract: This method is applicable for routine monitoring of patients' VRZ plasma level with fast and accurate runtime to assess CYP2C19 genotype.

Cited by 14 publications

References 24 publications

Impact ofCYP2C19,CYP3A4,ABCB1, andFMO3genotypes on plasma voriconazole in Thai patients with invasive fungal infections

Impact ofCYP2C19,CYP3A4,ABCB1, andFMO3genotypes on plasma voriconazole in Thai patients with invasive fungal infections

Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit

Determination of Voriconazole Plasma Concentration by HPLC Technique and Evaluating Its Association with Clinical Outcome and Adverse Effects in Patients with Invasive Aspergillosis

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