Introduction
Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in hospitalized patients, especially in children with primary and secondary immunodeficiency [1]. Aspergillus and Candida species are the most common opportunistic fungal pathogens. Currently, a variety of antifungal agents are available for the treatment of IFIs.
Voriconazole is a synthetic second-generation triazole antifungal agent with potent broad-spectrum antifungal activity, it is recommended as a first choice for the treatment of invasive aspergillosis in children [2,3]. In addition, voriconazole is characterized by nonlinear pharmacokinetics and has a significant interindividual and intraindividual variation in drug exposure [4].
It has been confirmed that voriconazole is extensively metabolized by the hepatic cytochrome P450 (CYP) enzyme system [5], mainly by the CYP2C19 isoenzyme. Additionally, CYP2C9 and CYP3A4 are also involved in the metabolism of voriconazole [6,7]. The expression and/or catalytic activity of the CYP450 enzyme is constantly changing with age and result in a significant variation of voriconazole pharmacokinetics between children and adults [8].
Previous studies demonstrated that the genetic polymorphisms of CYP2C19, CYP2C9 and CYP3A4 were closely related to the differences of the voriconazole plasma concentrations in adults [9–11]. However, this relationship is little known in children. This study aimed to examine the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients.
Materials and methods
Study design and subjects
Pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections, admitted to the Affiliated Hospital of Guizhou Medical University from October 2018 to July 2020, were prospectively enrolled in this study. This study was approved by the Ethics Committee of the Affiliated Hospital of Guizhou Medical University (approval #2018-83-01). The legal guardians of the children provided the written Informed Consent.
The subjects, from 2 to 14 years of age (<50 kg), were diagnosed with invasive fungal diseases (IFD) in line with the Diagnostic Criteria and Principles of Treatment for Invasive Fungal Diseases in Patients with Hematologic/Malignant diseases 2017 (5th Edition) [12]. According to the diagnostic criteria, patients were defined as proven, probable and possible IFD on the basis of the evidence provided by histopathologic/cytologic, culture, radiographic and biomarker examinations. The patients administered initial dose of voriconazole according to relevant guidelines [13,14], i.e. 9 mg/kg of oral voriconazole (max 350 mg tablets) q12h. A blood sample was obtained to detect the minimal steady-state plasma concentration on the sixth day of treatment, and voriconazole plasma concentrations were recorded and enrolled in our study. Then the further dose of voriconazole was adjusted according to the therapeutic drug monitoring (TDM) during the treatment.
In this study, patients who met the following criteria before the initial blood sampling were excluded [13]: (1) alanine aminotransferase or aspartate transaminase levels are three times above its upper limits; alkaline phosphatase or gamma-glutamyl transferase levels are 2.5 times above its upper limits; total bilirubin levels 1.5 times are above its upper limits, (2) serum creatinine or serum urea levels are above its upper limits.
Genotyping
Peripheral venous blood (2 ml) was drawn from each enrolled child and placed in an EDTA anticoagulant tube. DNA was extracted according to the instructions of the DNA Extraction Kit (CoWin Biotech, Beijing, China) and stored at −20°C for later use. Real-time fluorescence PCR with TaqMan probes was performed to test CYP2C19 [CYP2C19*2 (c.681 G > A; rs4244285), CYP2C19*3 (c.636 G > A; rs4986893), and CYP2C19*17 (c.-806 C > T; rs12248560)], CYP2C9 [CYP2C9*3 (c.1075 A > C; rs1057910), CYP2C9*13 (c.269 T > C; rs72558187)] and CYP3A4 [CYP3A4*22 (c.522-191 C > T; rs35599367), CYP3A4 (c.671-202 C > T; rs4646437)] for genotyping. PCR amplification was performed twice at 95°C for 2.5 min, followed by 35 cycles of 94°C for 15 s and 65°C for 55 s. According to the CYP2C19 genotypes, the pediatric patients were divided into five groups: ultra-rapid metabolizer (UM) (i.e. CYP2C19*17/*17), rapid metabolizer (RM) (i.e. CYP2C19*1/*17), normal metabolizer (NM) (i.e. CYP2C19*1/*1), intermediate metabolizer (IM) (i.e. CYP2C19*1/*2, CYP2C19*1/*3, or CYP2C19*2/*17) and poor metabolizer (PM) (i.e. CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3) [15].
Plasma voriconazole concentration determination
Peripheral venous blood samples were collected from the pediatric patients within 2 h before drug administration and centrifuged at 3000 r/min for 10 min at 4°C. The resulting supernatants were collected and supplemented with the fluconazole internal standard. The proteins were precipitated using acetonitrile, and the samples were centrifuged at 13 000 r/min for 10 min at 4°C. The supernatants were blow-dried with nitrogen and analyzed by UPLC-MS/MS. The UPLC and mass spectrometer conditions were as follows. The chromatography column was BEH C18 (2.1 Ă— 50 mm, 1.7 μm; Waters, Milford, Massachusetts, USA). The mobile phase consists of solvent A (0.1% formic acid in acetonitrile) and solvent B (0.1% formic acid in water) and gradient elution was performed. The column temperature was adjusted to 40°C, and the flow rate was 0.3 mL/min. 2 μL sample was totally loaded, and the collection time was 5 min. The detection was performed on a TSQ Enduratriple quadrupole tandem mass spectrometer coupled with electrospray ionization interface under positive-ion multiple reaction monitoring mode with molecular ion signal of m/z 350.112→281 for voriconazole and m/z 307.112→238 for fluconazole (IS), respectively.
The method was linear over the range of 50–10 000 ng/mL for voriconazole. With the peak area ratio of voriconazole to internal standard on the vertical axis and the concentration on the horizontal axis, a standard curve equation (y = 0.0038x - 0.0543, r2 = 0.9980; n = 8) was obtained by the least square method, which basically covered the range of trough plasma levels that might appear in the clinical practice. The lower limit of quantification (LLOQ) achieved in our study was established as 50 ng/mL for voriconazole, with relative SD (RSD) values <15%.
All the accuracies and precisions of intra- and inter-day were less than 15%, the extraction recovery was between 84.27% and 105.78%, and no matrix effect was observed in this method. RSD values of the short-term stability (at room temperature for 24 h), the long-term stability (at −80°C for up to 60 days) and the three complete freeze-thaw cycles (at −20 °C to room temperature) were lower than 8%. Finally, the method was conformed with the bioanalytical method validation of acceptance criteria and recommendations of Chinese Pharmacopoeia.
Statistical analysis
Statistical analyses were performed using SPSS, version 16.0 (IBM, Armonk, New York, USA). Data were presented as the mean ± SD. The t test was used to compare the voriconazole plasma concentrations between allele noncarriers and carriers. The trough plasma concentrations among different CYP2C19 metabolizer phenotypes were analyzed by One-way ANOVA with Tamhane post hoc. Multiple linear regression analysis was used to identify the determinants contributing to the variability of voriconazole plasma concentration. The comparisons of the incidence of adverse events in different CYP2C19 metabolizer phenotypes were analyzed by Chi-square test. P value of <0.05 was considered statistically significant in our study.
Results
Characteristics of the patients
Sixty-eight pediatric patients were included in this study. Table 1 summarized their demographic characteristics, hematological diagnoses, patient biochemical indexes (ALT levels, AST levels, ALP levels, GGT levels, TBIL levels, serum creatinine levels and serum urea levels) and concomitant medication. All patients received gene polymorphism tests and voriconazole plasma concentration monitoring. The average plasma concentration in all patients was 2751.8 ± 2906.4 ng/mL.
Table 1 -
Characteristics of the patients
| Characteristics |
Value for characteristics |
| Total patients |
68 |
| Age, year |
6.5 ± 3.7 (1.3–14) |
| Weight, kg |
23.2 ± 10.8 (9–48) |
| Sex |
|
|  Men |
38 (55.9%) |
|  Women |
30 (44.1%) |
| Clinical diagnosis |
|
|  Acute lymphoblastic leukemia |
51 (75.0%) |
|  β-thalassemia |
5 (7.3%) |
|  Acute myelogenous leukemia |
6 (8.8%) |
|  Aplastic anemia |
3 (4.4%) |
|  Neuroblastoma |
2 (3.0%) |
|  Acute promyelocytic leukemia |
1 (1.5%) |
| Biochemical indexa |
|
|  ALT levels, U/L |
33.5 ± 29.0 (4.8–140.0) |
|  AST levels, U/L |
30.3 ± 22.4 (6.6–137.0) |
|  ALP levels, U/L |
140.9 ± 58.3 (48.0–306.0) |
|  GGT levels, U/L |
41.7 ± 33.9 (7.9–146.0) |
|  TBIL levels, μmol/L |
12.6 ± 7.9 (4.1–34.1) |
|  Serum creatinine levels, μmol/L |
21.7 ± 8.3 (4.8–39.0) |
|  Serum urea levels, mmol/L |
5.3 ± 1.8 (1.4–8.9) |
| Concomitant medicationb |
|
|  Glucocorticoids(prednison/methylprednisolone/dexamethasone) |
25(12/2/11) |
|  Proton pump inhibitors(omeprazole/pantoprazole) |
7(2/5) |
|  Average plasma concentration, ng/mL |
2751.8 ± 2906.4 (15.0–9989.0) |
aALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP alkaline phosphatase; GGT, gamma-glutamyl transferase; TBIL, total bilirubin.
bIn this study, concomitant medications reported to have drug interactions with voriconazole were glucocorticoids and proton pump inhibitors.
Effect of CYP2C19 gene polymorphisms on voriconazole plasma concentration
Three single-nucleotide polymorphisms (SNPs) in CYP2C19 including CYP2C19*2, CYP2C19*3 and CYP2C19*17 were selected to detect the genotypes. The results showed that 35 patients (51.5%) were CYP2C19*2 allele non-carriers, 33 patients (48.5%) were CYP2C19*2 allele carriers (27 heterozygous and 6 homozygous individuals). The mean steady-state trough concentrations were 1331.4 ± 1741.9 ng/mL and 4155.8 ± 3232.1 ng/mL in noncarriers and carriers, respectively. The statistical analysis revealed that CYP2C19*2 allele noncarriers presented significantly lower voriconazole plasma concentrations than carriers (P < 0.0001; Fig. 1).
;)
Fig. 1: Voriconazole plasma concentration in CYP2C19*2 allele noncarriers or carriers.
Additionally, 57 patients (83.8%) were CYP2C19*3 allele noncarriers and 11 patients (16.2%) with heterozygous or homozygous for CYP2C19*3 in this study. Trough concentrations were significantly lower in CYP2C19*3 allele noncarriers compared with carriers (2315.7 ± 2642.9 ng/mL vs. 5011.9 ± 3283.3 ng/mL, P = 0.004; Fig. 2).
Fig. 2: Voriconazole plasma concentration in CYP2C19*3 allele noncarriers or carriers.
On the basis of the current genotyping results, no patient was found carrying CYP2C19*17 allele in the enrolled population.
Effect of CYP2C9 gene polymorphisms on voriconazole plasma concentration
CYP2C9*3 and CYP2C9*13 alleles in CYP2C9 were selected in the present study. The results demonstrated that 89.7% (61 patients) of the patients were CYP2C9*3 allele noncarriers, 10.3% (7 patients) were heterozygous for CYP2C9*3. The homozygous mutation was not found in our cohort. The voriconazole plasma concentrations were 2878.3 ± 2900.1 ng/mL and 1650.0 ± 2940.4 ng/mL in noncarriers and heterozygous carriers, respectively. The statistical analysis indicated that there was no significant difference in trough concentration between the non-carriers and heterozygous carriers (P = 0.293; Fig. 3). Moreover, expression of CYP2C9*3 allele did not affect the voriconazole plasma concentrations when patients were stratified on CYP2C19*1/*1 phenotype (CYP2C9*3 noncarriers: 904.3 ± 169.6 ng/mL, n = 25; CYP2C9*3 carriers: 465.5 ± 152.9 ng/mL, n = 4, P = 0.321). Genotyping data showed that mutation of CYP2C9*13 allele was not detected.
Fig. 3: Voriconazole plasma concentration in CYP2C9*3 allele noncarriers or carriers
Effect of CYP3A4 gene polymorphisms on voriconazole plasma concentration
In addition to CYP2C19 and CYP2C9, rs4646437 and CYP3A4*22 in CYP3A4 were also selected to detect the genotypes. Analysis of the genotyping assay showed that 47 children (69.1%) were noncarriers of rs4646437 variant, 18 children (26.5%) were heterozygous carriers for rs4646437 variant and only three children (4.4%) were homozygous carriers for rs4646437 variant. Although the mutant allele frequency of rs4646437 was high, no significant difference in voriconazole plasma levels between the non-carriers and carriers (2738.8 ± 2833.9 ng/mL vs. 2780.8 ± 3134.6 ng/mL, P = 0.942; Fig. 4) was observed. Similarly, when patients were stratified on CYP2C19*1/*1 phenotype, the mutation of rs4646437 did not affect the voriconazole plasma levels (noncarriers of rs4646437 variant: 793.3 ± 184.8 ng/mL, n = 22; carriers of rs4646437 variant: 1002.3 ± 227.9 ng/mL, n = 7, P = 0.560). However, no CYP3A4*22 allele carrier was observed in our research.
Fig. 4: Voriconazole plasma concentration in noncarriers or carriers of CYP3A4 rs4646437 variant.
Multiple linear regression model
On the basis of the results of univariate analysis, factors that might affect voriconazole plasma concentration, including age, weight, glucocorticoid, proton pump inhibitor, CYP2C19*2 and CYP2C19*3 alleles, were integrated in the multiple linear regression model. CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.413; P < 0.0001). Details of Multiple Linear Regression Model were presented in Table 2.
Table 2 -
Model of multiple linear regression
| Variables |
β
|
P value |
| Age |
0.088 |
0.679 |
| Weight |
−0.215 |
0.313 |
| Glucocorticoid |
0.101 |
0.328 |
| Proton pump inhibitor |
−0.054 |
0.608 |
|
CYP2C19*2 allele |
0.536 |
<0.0001 |
|
CYP2C19*3 allele |
0.386 |
<0.0001 |
Relationship between voriconazole plasma concentrations and the CYP2C19 metabolizer phenotypes
For CYP2C19, 42.6% (n = 29), 41.2% (n = 28) and 16.2% (n = 11) of patients were classified as NM, IM, and PM groups, respectively. The corresponding trough concentrations were 843.7 ± 806.2, 3633.5 ± 2806.8, and 5538.0 ± 3497.6 ng/mL. UM and RM were not detected in our cohort. Table 3 summarizes the distribution of metabolizer phenotypes and CYP2C19 genotypes. Trough concentration of voriconazole was significantly lower in NM group compared with IM (P < 0.0001) and PM (P = 0.004) groups, with no significant difference between IM and PM groups (P = 0.335; Fig. 5).
Table 3 -
Distribution of metabolizer phenotypes and
CYP2C19 genotypes
| Metabolizer phenotypes |
N (%) |
Genotypes |
N (%) |
| NM |
29 (42.6) |
*1/*1 |
29 (42.6) |
| IM |
28 (41.2) |
*1/*2 |
22 (32.4) |
|
|
*1/*3 |
6 (8.8) |
| PM |
11 (16.2) |
*2/*2 |
6 (8.8) |
|
|
*2/*3 |
5 (7.4) |
NM, normal metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.
Fig. 5: Voriconazole plasma concentration in different CYP2C19 metabolizer phenotypes.
Safety of voriconazole therapy
Adverse event was closely monitored and recorded in this research. As described in Table 4, liver dysfunction was the most common drug-related adverse event, and the total incidence of adverse events was significantly higher in PM group compared with IM group (P = 0.018), particularly the elevation of alkaline phosphatase increased (P = 0.030). Other adverse events included nervous system/psychiatric disorders, visual disturbance, gastrointestinal effects and skin disorders were not observed.
Table 4 -
Adverse events in 68 patients treated with
voriconazole
|
NM (N = 29) |
IM (N = 28) |
PM (N = 11) |
P value |
| Number of patients with adverse events |
21 |
14# |
10 |
0.032 |
| Alanine aminotransferase increaseda |
5 |
6 |
1 |
0.659 |
| Aspartate aminotransferase increaseda |
4 |
4 |
1 |
0.905 |
| Alkaline phosphatase increasedb |
18## |
7# |
7 |
0.01 |
| Gamma-glutamyl transferase increasedb |
6 |
6 |
1 |
0.651 |
| Total bilirubin increasedc |
2 |
2 |
1 |
0.971 |
| Otherd |
0 |
0 |
0 |
/ |
aAlanine aminotransferase or aspartate transaminase levels lower than three times upper the limit of normal.
bAlkaline phosphatase or gamma-glutamyl transferase levels lower than 2.5 times upper the limit of normal.
cTotal bilirubin levels lower than 1.5 times upper the limit of normal.
dOther adverse events included nervous system/psychiatric disorders, visual disturbance, gastrointestinal effects and skin disorders.
#P < 0.05 for the intermediate metabolizer (IM) vs. poor metabolizer (PM).
##P < 0.05 for the normal metabolizer (NM) vs. intermediate metabolizer (IM).
Discussion
Voriconazole is a broad-spectrum antifungal agent which is widely used for the treatment of invasive aspergillosis and invasive candidiasis in pediatric clinical practice [2,14,16]. However, the physiological particularities of children cause greater variability in voriconazole administration compared with adults [17]. Consequently, it is very necessary to monitor voriconazole plasma concentrations. It has been demonstrated that the variability of voriconazole plasma concentrations was mainly affected by the polymorphisms of CYP2C19, CYP2C9 and CYP3A4, few data are available for children [18–20]. Therefore, this study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in pediatric patients. Our results suggested that the polymorphisms of CYP2C19 is a major factor that affected plasma concentrations of voriconazole, while CYP2C9 and CYP3A4 gene polymorphisms showed no detectable impacts.
CYP2C19 is the major isoenzyme of voriconazole metabolism. Some variant CYP2C19 alleles have been identified that could affect the plasma concentrations of voriconazole, such as CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles. Hence, the CYP2C19 genotype test has been recommended [15]. Patients who were carrying CYP2C19*2 and/or CYP2C19*3 allele exhibit lower metabolic activity, and are associated with elevated voriconazole concentrations compared with the wild-type carriers [21,22]. Conversely, the CYP2C19*17 allele carriers exhibit increased metabolic activity and are associated with lower voriconazole concentrations [23]. Similar results were also observed in pediatric patients [18–20]. In this study, voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than those with wild-type carriers. Because of the low frequency in Chinese subjects (<4%) [23], CYP2C19*17 allele carriers were not observed in our study.
The CYP2C9 isoenzyme is mainly responsible for the oxidative metabolism of several clinically important compounds, including warfarin, phenytoin, losartan, torsemide, etc. and the variability of plasma concentrations was mainly related to CYP2C9*2 and CYP2C9*3 alleles [25]. Voriconazole is primarily metabolized by the CYP2C19 enzyme, with contribution by CYP2C9. However, the relationship between the CYP2C9 gene polymorphisms and voriconazole plasma levels was not clear in children. In this study, CYP2C9*2 allele was not tested here because of the low frequency in Asian populations (<0.1%) [26,27]. For CYP2C9*3, the allele frequency is 10.3%, and there was no significant difference in voriconazole plasma concentration between the non-carriers and carriers. As a new variant, CYP2C9 allele, that was first discovered in the Chinese, CYP2C9*13 allele is very important in determining CYP2C9 metabolic capability. A previous study demonstrated that CYP2C9*13 allele was correlated with reduced plasma clearance of drugs [28,29]. However, it was not clear whether the CYP2C9*13 allele could affect the voriconazole plasma concentrations. We sought to find the association between the CYP2C9*13 allele and voriconazole plasma levels in this study. Unfortunately, the CYP2C9*13 allele was not detected in all patients.
CYP3A4 isoenzyme plays an important role in oxidative metabolism of voriconazole. It has been demonstrated that CYP3A4 genotypes could affect voriconazole exposure [30]. The CYP3A4*22 and rs4646437 were associated with higher plasma voriconazole concentrations [31,32]. However, no data are available describing the relationship between CYP3A4 gene polymorphisms and voriconazole plasma levels in pediatric patients. In this study, the allele frequency of CYP3A4 rs4646437 was 30.9%, but no significant difference in voriconazole plasma levels between the noncarriers and carriers. Our results corroborate a report by Chuwongwattana et al. [33]. In agreement with a previous study involving 86 Chinese subjects [34], the CYP3A4*22 allele carriers were not observed in this research.
The adverse events of voriconazole include hepatotoxicity, neurotoxicity and visual disorders, etc. This research suggested that the most common adverse event, hepatotoxicity, should be mainly focused on considering other events that occurred less frequently. Currently, the relationship between voriconazole blood concentration and hepatotoxicity still remains unclear in children. A previous meta-analysis showed that the incidence of hepatotoxicity was not associated with voriconazole plasma concentration [35]. However, Hanai et al. concluded that a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough concentration above 3.0 mg/L [36]. In our study, the incidence of hepatotoxicity was significantly higher in NM and PM groups compared with IM group. Factors that might contribute to this included the different definitions of hepatotoxicity, concomitant medication and small sample size.
This study had several limitations. First, the sample size was small, and all pediatric patients were selected from a single hospital. Second, all children were Chinese, restricting the generalizability of the results to other populations with different genetic backgrounds. Third, inflammation could also contribute to the pharmacokinetic variability of voriconazole, but the relationship between inflammation and voriconazole serum concentration was not further investigated in this research as the lack of available data. Moreover, only three enzymes were examined because they are considered the most significant players in voriconazole metabolism, but genome-wide studies may reveal additional polymorphisms affecting plasma voriconazole levels.
In conclusion, voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms instead of CYP2C9 and CYP3A4 gene polymorphisms.
Acknowledgements
This study was funded by the Guiyang Municipal Science and Technology Program (NO: Z.K.H.T. [2018]1-93).
J.Y. designed and coordinated the study, and revised the manuscript. X.Z. and Y.Y. collected blood samples. H.Z. and Z.W. performed the experiments. X.F. collected and analyzed the data, and wrote the manuscript draft. All authors reviewed the results and approved the final version of the manuscript.
Conflicts of interest
There are no conflicts of interest.
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