Effects of inflammation on voriconazole metabolism and peripheral blood trough concentration

doi:10.21203/rs.3.rs-3219646/v1

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Effects of inflammation on voriconazole metabolism and peripheral blood trough concentration

https://doi.org/10.21203/rs.3.rs-3219646/v1

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Background

The inner association of inflammation with voriconazole (VCZ) metabolism has not been fully investigated. This study further discussed the relationship between C-reactive protein (CRP) and voriconazole blood trough concentration, and provided reference for clinical rational use of voriconazole in the treatment of inflammatory diseases.

Objective

To investigate the influence of CRP on the trough concentration of voriconazole (VCZ) and provide reference for rational drug use in clinical practice.

Methods

The data of patients who used voriconazole in our hospital were analyzed retrospectively, and the plasma concentration of voriconazole was determined by High Performance Liquid Chromatography(HPLC). The effects of age, sex, liver function, kidney function and CRP on plasma concentration of voriconazole were analyzed, and the relationship between CRP and the plasma concentration of voriconazole was analyzed by using the ROC curve of the subjects.

Results

In total, 284 patients were included in the study. Gender, age and renal function had no obvious influence on the valley concentration of voriconazole.There was a significant correlation between ^{Glutamyltranspeptidase (GTP)} and voriconazole valley concentration (P = 0.00487). With the increase of CRP, the trough concentration of voriconazole also increased. In the ROC curve evaluation, the area under the diagnostic curve (AUC) with CRP value of the predictor is 0.7898 (95% CI = 0.7157 ~ 0.8639, P < 0.0001), and the corresponding optimal critical cut-off point was 37.7 mg/L, which indicated that when the CRP was 37.7 mg/L, the incidence of voriconazole blood trough concentration exceeding 5.0 mg/L was high.

Conclusion

The blood trough concentration of voriconazole is very different between human and human.. Inflammation is one of the factors affecting the concentration of voriconazole in blood. It can be predicted that the CRP value will be higher than 37.7 mg/L, and the blood concentration of voriconazole may be higher than 5.0 mg/L under the same loading dose. Therefore, it is suggested to pay attention to CRP in patients when voriconazole is used clinically. When it is higher than 37.7 mg/L, more attention should be paid to the blood trough concentration of voriconazole to avoid liver dysfunction and other more serious complications.

CRP

Voriconazole

Blood drug concentration

adverse effect

Fluconazole (VCZ) is a broad-spectrum antifungal drug and a first-line medication for the treatment of invasive aspergillosis. Multiple studies have shown that the trough concentration of VCZ is related to its efficacy and safety. After absorption, there is significant inter-individual variation in the blood concentration of VCZ^[1]. Low trough concentrations of VCZ (less than 1.0 mg/L) are associated with treatment failure, while high trough concentrations (more than 5.0 mg/L) are associated with increased risk of toxicity (hepatotoxicity, neurotoxicity, visual impairment, and rash). The development of individualized treatment strategies is an important research direction in the field of pharmacy, aiming to provide patients with more personalized and accurate drug treatment plans based on their individual characteristics and disease status. Some progress has been made in the development of personalized treatment strategies for VCZ, but there are still some limitations, including patient genetic characteristics, drug metabolism capacity, disease characteristics, and clinical manifestations. Another key factor is the polymorphism of the CYP2C19 gene, which is the main metabolic enzyme of VCZ and can lead to differences in the metabolism of VCZ among patients^[2–4]. However, these factors cannot fully explain the variability in VCZ metabolism.

Studies have found that the inflammatory state may affect the pharmacokinetics of fluconazole, including processes such as absorption, distribution, metabolism, and excretion. Infection or inflammation can lead to downregulation of various forms of cytochrome P450 enzymes. Downregulation of cytochrome P450 enzymes reduces the hepatic clearance rate of drugs metabolized by these enzymes. Because fluconazole is extensively metabolized by cytochrome P450 enzyme 2C19, inflammation may be one of the factors leading to liver cell variation and affecting the pharmacokinetics of fluconazole^{[5, 6]}. CRP is a commonly used inflammatory marker in clinical practice. It is a non-specific marker of acute inflammation that reflects the degree and process of the body's inflammatory response. Studies have shown that an elevated CRP level may lead to an increase in the trough blood concentration of fluconazole^{[7, 8]}. Therefore, monitoring CRP levels can help evaluate fluconazole treatment strategies and guide individualized treatment strategies. However, it should be noted that the current research results are inconsistent and there are limitations. The methods used in the study, the selection of study subjects, and other potential confounding factors may all affect the results. Therefore, further research and validation are still needed to understand the relationship between fluconazole and CRP. This article uses a retrospective study approach, and further research will help to comprehensively understand the relationship between fluconazole and CRP and provide more informative guidance for clinical practice.

Patients and Study Design

We retrospectively studied the medical records of inpatients treated with voriconazole in the Department of Hematology, Xiangya Hospital, Central South University from January 1, 2016 to February 1, 2021, and measured the steady-state blood valley concentration. Xiangya Hospital of Central South University is a large-scale comprehensive teaching hospital with 3,500 beds. This study strictly followed the Declaration of Helsinki, and was submitted to the Ethics Committee of Xiangya Hospital, Central South University. In this study, each patient's written informed consent was obtained.

Inclusion criteria: (1)Voriconazole was used in a loading dose for treatment, and the maintenance dose exceeds 2 days; (2) When no load is used, the dosage should be maintained for more than 3 days. Exclusion criteria: (1) Pregnant women; (2) Patients who received initial TDM after dose adjustment; (3) Patients lacking information about the route or dose of administration; (4) Patients whose voriconazole failed to reach steady state or underwent blood purification during blood collection process; (5) Patients who had used proton pump inhibitors during their treatment; (6) Patients are taking voriconazole in combination with CYP 450 inducers such as phenobarbital, rifampicin, phenytoin and carbamazepine, or CYP 450 inhibitors such as cimetidine, erythromycin and vinca alkaloids.

Data Collection

Through the electronic medical record system, the clinical data of patients were collected and the demographic data of patients were recorded(e.g., age, gender, etc.), and patients' liver function indicators, renal function indicators, CRP and so on.

VCZ trough concentration determination

Blood Collection

The VCZ was defined as the concentration obtained after 3 days of VCZ therapy with a loading dose of 6 mg/kg by intravenous administration, and maintenance dose of 4 mg/kg by intravenous administration, or sequentially taking VCZ orally (200 mg).

Chromatographic Test

The most of the described in the literature are the methods of liquid chromatography (LC) coupled with a spectrophotometer detector (HPLC/UV). Reagents: Voriconazole(China National Food and Drug Administration, batch number: 100862-201903), Estazolam (China National Food and Drug Administration, batch number: 171219-201003), Methanol (chromatographic purity, Anhui Tiandi High-purity Solvent Co., Ltd.) and purified water (prepared by Xiangya Hospital of Central South University); Chromatographic conditions: The chromatographic system, from Shimadzu, consisted of a LC-20 A pump, equipped with a 100 μl injection loop, and a programmable SPD-10 Av UV–vis absorbance detector. Separation for voriconazole was performed by Agilent Zorb Ax 3B-C18 (250 × 4.6 mm, 5 μm) analytical column with a mobile phase consisting of methanol: water (60: 40, v/v) set at a flow rate of 1.0 mL/min. The UV detection was set at 256 nm. The retention time of voriconazole and internal standard (estazolam) was found to be 9.6 and 8.2 min respectively. Standard curve: 195 µl blank plasma was precision added with 5 µl of voriconazole reference solution, and a series of plasma samples were prepared with different concentrations. According to the operation of blood sample pretreatment, the peak area ratio of estazolam was used to regress the concentration of voriconazole in plasma samples, and a regression equation was established (Y =0.5536 X+0.0037, r²=0.9997). Then, 200 µl plasma was accurately sucked into a 2 mL EP tube, 10 L of internal standard estazolam solution (50 μg/mL) was added and vortex mixed for 30 s. Add 1600 μl of mixed extract（N-hexane 1200 μl+ethyl acetate 400 μl）, vortex mixing for 1 min and centrifugation at 14500 rpm for 8 min. Then, 1400 μl supernatant was sucked into another EP tube, and volatilized at n 2 for 20 minutes. Then it was reconstituted with 50% methanol (150 μl), vortex-mixed for 30 seconds, and centrifuged at 14500 rpm for 3 minutes. Transfer 100 μl into the liner tube with a pipette, put the sample into the HPLC rack, and analyze it with the injection volume of 20 μl.

The linear range of the method was 0.313~10 μg/mL (Y = 0.5536 X+0.0037, r = 0.9997). LLOQ was 0.156 μg/mL, and S/N > 10. The precision, accuracy, matrix effect, recovery rate and stability meet the requirements of the bioanalysis method validation guidelines (summarized in supporting information).

Statistical Analysis

In this study, SPSS 22.0 medical software (SPSSInc, Chicago, Illinois, USA) was adopted for statistical analysis. The classified variables were compared with χ2 test or Fisher's exact test, and the continuous variables were compared with non-parametric Mann-Whitney U test or Kruskal-Wallis H test. Bonferroni method was used to analyze the difference between the groups, and receiver operating characteristic curve (ROC) curve was used to determine the relationship between CRP and voriconazole blood concentration. P < 0.05 indicated that the difference was statistically significant.

Patient Characteristics

A total of 284 patients were enrolled in this study, including 169 males (59.5%) and 115 females (40.5%) with the average age of (41.47, 22.58) years. Voriconazole was most commonly used in empirical treatment (63.0%), followed by targeted treatment (22.2%) and preventive treatment (14.8%). Voriconazole was highly available for oral bioavailability and was administered orally (64.8%) or intravenously (35.2%). Hematologic malignancies are the most common potential diseases in drug treatment of our patient, and the common site of infection is the lung(Table 1).

Gender and Age

Independent sample t test of voriconazole valley concentration according to sex did not show a significant difference. One-way ANOVA of voriconazole valley concentration according to age group showed significant difference. Bonferroni method was used to analyze the differences between the groups, and it was found that there was a significant differences between the ≤ 45 year-old group and > 60 year-old group (P = 0.000), and there were significant differences in the 45~60 year-old group and > 60 year-old group (P = 0.027). (Table 2)

Liver and Renal Function

The total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase(AST), and the blood trough concentration of voriconazole in patients were analyzed by one-way ANOVA, and the result showed no significant difference. The one-way ANOVA of serum concentration of Glutamyltranspeptidase (GTP) and voriconazole showed significant difference (P = 0.0487). The one-way ANOVA of the blood trough concentrations of blood urea nitrogen (BUN), Creatinine (CRE) and voriconazole of our patient showed no significant difference (P > 0.005)(Table 3).

The concentration of voriconazole valley was divided into groups according to the normal range set by blood biochemical indexes, and the normal range of total bilirubin(TBIL): 0~25 μmol/L; alanine aminotransferase (ALT): 9.0~50.0 U/L; aspartate aminotransferase (AST): 15.0~40.0 U/L; blood urea nitrogen (BUN): 3.10~8.0 mmol/L; creatinine (CRE): 41.0~111.0 μmol/L. According to the subgroup of total bilirubin, the concentration of voriconazole valley was tested by independent sample T-test, and the subgroup of other indexes was analyzed by one-way ANOVA. The results showed that TBIL, ALT, AST and BUN were not independent factors of valley concentration of voriconazole, but Cr was an independent factor. Bonferroni analysis of the differences between groups showed that there was a significant difference in the concentration of voriconazole between Cre < 41.0 mol/L and Cre 41.0~111.0 mol/L (P = 0.040), and there was a significant difference in the concentration of voriconazole between Cre < 41.0 mol/L and Cre > 111.0 mol/L(P = 0.040).(Table 4).

Distribution of Blood Trough Concentration of VCZ

According to previous multi-center clinical studies and preliminary clinical observations^[9,10],voriconazole with a blood concentration ranging from 1.0 μg/mL~1 5.0 μg/mLhas the best clinical efficacy and a low incidence of adverse reactions. Therefore, according to this range, the blood concentration was analyzed in groups. Among them, 174 patients had blood drug concentrations within the range of 1.0 μg/mL~5.0 μg/mL, 71 cases had < 1.0 μg/mL, and 39 cases had > 5.0 μg/mL.

Analysis of correlation between inflammatory indexes and voriconazole

Of the six indexes, CRP and GTP turned out to havea significant overall association with VCZ trough concentrations: CRP: r = 0.11, P < 0.0001, 284 observations; GOT: r = 0.040, P < 0.05, 98 observations (Figure 1). CRP levels showed an overall correlation with VCZ trough concentrations: r = 0.11, P < 0.0001, 284 observations. Children(0~14 years old): r = 0.24, P = 0.0009, 42 observations; Adult(15~65 years old): r = 0.11, P < 0.0001, 155 observations; Snior citizen (Over 65 years old): r = 0.077, P = 0.0025, 65 observations(Figure 2). According to CRP value, the concentration of voriconazole was divided into three groups: CRP < 40 mg/L, 40~200 mg/Land > 200 mg/L, One-way ANOVA analysis showed that there was significant difference, P < 0.001(Table 5). The correlation between CRP and VCZ valley concentration show that the steady-state valley concentration of voriconazole increased with the increase of CRP value(Figure 3). According to the effective range of voriconazole valley concentration from 1.0 μg/mL to 5.0 μg/mL, patients were divided into window group and super window group(VCZ C_min ≥ 5.0 μg/mL). The receiver operating characteristic curve (ROC) was constructed by using CRP values of our patient as the predicted value. The area under the curve (AUC) was 0.7898 (95% CI = 0.7157~0.8639, P < 0.0001), and the corresponding optimal critical tangent point is 37.7 mg/L(Figure 4).

As a first-line drug for the treatment of invasive aspergillosis, there is significant inter-individual variability in the trough blood concentration of fluconazole. Of the 284 patients included in this study, 174 had blood concentrations of 1.0 μg/mL to 5.0 μg/mL, 71 had concentrations < 1.0 μg/mL, and 39 had concentrations > 5.0 μg/mL. Based on previous multicenter clinical studies and preliminary clinical observations, the optimal clinical efficacy and a lower incidence of adverse reactions occurs when the trough blood concentration of fluconazole is in the range of 1.0 μg/mL to 5.0 μg/mL. Common adverse reactions of fluconazole include abnormal liver function and neurological abnormalities, which are related to the level of drug concentration in the body. This study conducted a correlation analysis between liver function indicators and the trough blood concentration of fluconazole, and found a correlation between glutamate transpeptidase and the trough blood concentration of fluconazole (P = 0.0487). It is speculated that an increase in the trough blood concentration of fluconazole may be related to the occurrence of adverse reactions such as abnormal liver function.

The incidence of deep fungal infections is increasing in patients with malignant hematological diseases and tumors, with a variety of fungal species causing systemic infections in various organ systems, posing a serious threat to the lives of these high-risk populations and seriously affecting patient prognosis, and thus must be given sufficient attention[11]. Infection or inflammation can affect drug pharmacokinetics by influencing drug-metabolizing enzymes and transporters. CYP450 enzymes are important drug-metabolizing enzymes in the body, which decrease in activity during infection or inflammation, leading to a decrease in the clearance of drugs primarily metabolized by CYP450 enzymes, resulting in drug exposure or increased concentrations in the body. The mechanism of decreased enzyme activity is that pro-inflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) down-regulate CYP450 enzyme gene transcription, reduce mRNA synthesis, and decrease CYP450 enzyme protein content [8, 12, 13].

CRP is an acute-phase protein secreted by liver cells under the action of pro-inflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), and starts to increase 4-6 hours after the initiation of infection or inflammation, peaking at 24~48 hours[14, 15]. Although CRP is a delayed response to the inflammatory state, the steady-state trough concentration of voriconazole is measured 24 hours to 7 days after drug administration. Therefore, CRP at this time can reflect the inflammatory state. Single-factor analysis of variance was performed using patient CRP and voriconazole blood trough concentrations, and the results showed significant differences (P < 0.0001), indicating a correlation between voriconazole plasma trough concentrations and CRP levels. According to CRP values, patients were divided into three groups: CRP < 40 mg/L, 40~200 mg/L, and > 200 mg/L for analysis, suggesting that individual differences in voriconazole blood trough concentrations under different infectious conditions are more pronounced.

The receiver operating characteristic (ROC) curve was used to investigate the effect of CRP levels on the occurrence of voriconazole blood concentrations exceeding 5.0 μg/mL. By continuously changing the diagnostic threshold, multiple pairs of sensitivity (true positive rate) and 1-specificity (false positive rate) were obtained. The former was used as the horizontal axis and the latter as the vertical axis to plot the ROC curve. The statistical method was integrated to obtain the area under the curve (AUC), which represents the predictive accuracy of the critical value threshold point. The value range is 0.5~1.0, and the closer the value is to 1, the higher the diagnostic value. The point at the top left of the ROC curve is the point where the sum of sensitivity and specificity is maximum and the Youden index is also maximum. It takes into account both sensitivity and specificity, and the corresponding CRP value is the optimal critical value cutoff point. A P-value of less than 0.05 indicates a statistically significant difference. The ROC curve analysis suggested that when CRP is greater than 37.7 mg/L, the voriconazole trough concentration will be higher than 5.0 μg/mL.

In summary, current clinical research mainly focuses on the correlation between voriconazole and CRP, exploring its application in voriconazole dosing selection, pharmacokinetics, therapeutic effects, and personalized treatment. The goal of these studies is to provide more accurate guidance for voriconazole treatment, improve treatment efficacy, and reduce the occurrence of adverse reactions. However, further research is needed to validate and expand these findings, and deepen our understanding of the correlation between voriconazole and CRP. This study also confirms that inflammation is one of the significant influencing factors. The increase in the blood concentration of voriconazole may cause liver function abnormalities, and CRP is a commonly used indicator of inflammation in clinical practice. The study results suggest that when the CRP value is higher than 37.7 mg/L, it can predict that under the same loading dose, the trough concentration of voriconazole blood may be mostly higher than 5.0 μg/mL. Therefore, it is recommended that clinicians pay attention to patients' CRP during the use of voriconazole. When CRP is higher than 37.7 mg/L, more attention should be paid to the trough concentration of voriconazole blood to avoid more severe adverse reactions such as liver function abnormalities.

The blood trough concentration of voriconazole is very different between human and human. Inflammation is one of the factors affecting the concentration of voriconazole in blood. It can be predicted that the CRP value will be higher than 37.7 mg/L, and the blood concentration of voriconazole may be higher than 5.0 mg/L under the same loading dose. Therefore, it is suggested to pay attention to CRP in patients when voriconazole is used clinically. When it is higher than 37.7 mg/L, more attention should be paid to the blood trough concentration of voriconazole to avoid liver dysfunction and other more serious complications.

VCZ: voriconazole

CRP: C-reactive protein

HPLC: High Performance Liquid Chromatography

GTP: Glutamyltranspeptidase

AUC: Area under the diagnostic curve

TBIL: Total bilirubin

ALT: alanine aminotransferase

AST: aspartate aminotransferase

BUN: blood urea nitrogen

CRE: Creatinine

Availability of data and materials

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Acknowledgements

The authors thank the Department of Pharmacy, Xiangya Hospital, Central South University, Therapeutic drug monitoring laboratory for their support of this endeavor.

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Funding

This work was supported by the Fund for the Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, China (2017TP1037).

Author information

Authors and Affiliations

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, PR China

Qi Huang, Ting-ting Dai, Shao Liu & Yueping Jiang

Department of Oncology, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, P.R. China

Qiong Liu

Department of Pharmacy, the Third People's Hospital of Yunnan Province, Kunming, 650011, Yunnan, P.R. China

Jing Wen

Contributions

HQ and WJ designed the study, performed the data analysis, and drafted the manuscript; HQ searched the data and did the detection; HQ, WJ, DTT, LS, LQ and JYP did the detection; HQ, WJ, LS, JYP and LQ searched the data. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Qiong Liu & Yueping Jiang

Ethics declarations

Ethics Statement

The studies involving human participants were reviewed and approved by Ethics Committee of the Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Table 1 Basic Information of Patients (n=284).

project	numerical value	project	numerical value
Gender [Cases (%)]		Disease type [case (%)]
man	169(59.5)	Acute non-lymphocytic leukemia	68(23.9)
woman	115(40.5)	Acute lymphocytic leukemia	47(16.5)
Age [Cases (%)]		Severe pneumonia	38(13.4)
≤45 years old	154(54.2)	aplastic anaemia	17(6.0)
45–60 years old	64(22.5)	lymphoma	16(5.6)
> 60 years	66(23.2)	Myelodysplastic syndrome	12(4.2)
VCZ concentration (μg/mL)	2.944±2.801	Solid malignant tumor	11(3.9)
Total bilirubin (μmo/L^-1)	13.46±19.53	Chronic obstructive pulmonary disease	11(3.9)
Alanine aminotransferase (U/L)	47. 15±101	Mediterranean anemia	8(2.8)
Aspartate aminotransferase (U/L)	46.77±87.28	Hemophagocytic syndrome	6(2.1)
Urea (mmol/L)	7.295±5.979	ANCA-associated vasculitis	4(1.4)
Creatinine (μmol/L)	80.73±58.37	Acute myeloid leukemia	4(1.4)
C-reactive protein (mg/L)	66.99±84.21	Chronic myelomonocytic leukemia	4(1.4)
Administration method [case (%)]		POEMS syndrome	3(1.1)
take orally	184(64.8)	Systemic lupus erythematosus	2(0.7)
Intravenous drug use	100(35.2)	other	33(11.6)
Therapeutic purpose [case (%)]
Empirical treatment	179(63.0)
Target treatment	63(22.2)
Preventive treatment	42(14.8)

Table 2 Effects of gender and age on voriconazole trough concentrations (n=284).

project	Cases (%)	VCZ concentration (μg/mL)	P value
gender
man	169 (59.5)	2.87 ± 2.33	0.599
woman	115 (40.5)	3.05 ± 3.38	0.599
age
≤45 years old	154 (54.2)	2.30 ± 2.31	0.000
45~60 years old	64 (22.5)	3.08 ± 3.65
> 60 years	66 (23.2)	4.32 ± 2.40

Table 3 Single factor analysis of liver function and voriconazole blood trough concentration.

Liver and renal function index	Biochemical indicator concentration ()	VCZ trough concentration ()	P value
GTP (U/L)	123.2 ± 174.1	2.03 ± 2.02	0.0487
ALT (U/L)	47.15 ± 101.0	2.79 ± 2.82	0.6532
AST (U/L)	46.77 ± 87.28	2.80 ± 2.79	0.3661
BUN (mmol/L)	7.295 ± 5.979	2.83 ± 2.85	0.5769
Cr (μmol/L)	80.73 ± 58.37	2.85 ± 2.86	0.6960

Table 4 Impacts of liver and kidney functions on voriconazole trough concentration (n=284).

project	Cases (%)	VCZ concentration (μg/mL)	P value
TBIL (μmol/L)
≤25.0	258 (91.8)	2.94 ± 2.91	0.941
＞25.0	23 (8.2)	2.99 ± 1.48	0.941
ALT (U/L)
＜9.0	42 (14.9)	2.16 ± 1.72	0.126
9.0~50.0	191 (68.0)	3.13 ± 3.03
＞50.0	48 (17.1)	2.90 ± 2.60
AST (U/L)
＜15.0	61 (21.6)	2.64 ± 2.64	0.246
15.0~40.0	153 (54.3)	2.86 ± 2.81
＞40.0	68 (24.1)	3.42±2.93
BUN (mmol/L)
＜3.1	57 (20.4)	3.22 ± 3.99	0.213
3.10~8.0	151 (54.1)	2.68 ± 2.25
＞8.0	71 (25.5)	3.32 ± 2.75
Cr (μmol/L)
＜41.0	27 (9.6)	1.46 ± 1.83	0.014
41.0~111.0	224 (80.0)	3.08 ± 2.90
＞111.0	29 (10.4)	3.31 ± 2.59

Table 5 Effect of CRP on VCZ valley concentration(n=284).

CRP (mg /L)	Count(%)	VCZ concentration(μg/mL)	P value
＜40	150	2.18 ± 1.89
40~200	116	3.46 ± 3.30	＜0.001
＞200	17	6.25 ± 2.84

No competing interests reported.

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Effects of inflammation on voriconazole metabolism and peripheral blood trough concentration

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