Research Article Pharmacology DOI: 10.1159/000510327
Received: May 28, 2020 Accepted: July 20, 2020 Published online: September 30, 2020
Predictive Value of FMO3 Variants on Plasma Disposition and Adverse Reactions of Oral Voriconazole in Febrile Neutropenia Xiaokang Wang a Jingjing Zhao b Ting Wen c Xueyi Liao a Bin Luo b
aDepartment
of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China; bDepartment of Pharmacy, Guangdong Women and Children Hospital, Guangzhou, China; cDepartment of Pharmacology, Wuhan Mental Health Center Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
Abstract Background and Objectives: With the increasing number of patients with febrile neutropenia (FN), voriconazole (VRC) has been widely used in hospitals for first-line treatment of FN. The study was designed for evaluating the influence of FMO3 mutation on the plasma disposition and adverse reactions of VRC in FN. Materials and Methods: A single-center observational study was conducted in the inpatient ward for 4 years. The genotypes of FMO3 and cytochrome P450 (CYP) 2C19 were detected by PCR-restriction fragment length polymorphism. Patients with neutropenia were screened according to the CYP2C19 metabolic phenotype and other inclusion criteria. Five days after empirical administration of VRC, blood concentrations of VRC and nitrogen oxides in patients’ blood were determined by liquid chromatographyelectrospray tandem mass spectrometry (LC-ESI MS/MS). Serum parameters and clinical adverse reaction symptoms in the medical records were collected and statistically analyzed. Results: A total of 165 patients with neutropenia with
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© 2020 S. Karger AG, Basel
the intermediate metabolic phenotype of CYP2C19 were screened. At the initial stage of oral VRC treatment, patients with the FMO3 E308G genotype had a poorer plasma disposal ability to VRC than those with the wide type of FMO3 (WT) genotype (p = 0.0005). Moreover, patients with the FMO3 E308G genotype were more likely to have adverse drug reactions and abnormal serum parameters after receiving VRC treatment. For example, the serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028), the abnormal level of total bilirubin in the FMO3 E308G genotype group was significantly higher than that in the WT group (p = 0.049), and the aspartate aminotransferase level in the E308G group was significantly higher than that in the WT group (p = 0.05). The incidence of atopic dermatitis and visual impairment in the FMO3 E308G genotype group was 67 and 75%, respectively, and the incidences of peripheral neuroedema, headache, and diarrhea were 57, 50, and 60%, respectively, which were significantly different from those in the WT group. Conclusion: FMO3 E308G reduces the activity of the FMO3 enzyme by decreasing the metabolic ability of VRC, which increases the plasma concentration of VRC and may also lead to adverse reactions in patients with FN. © 2020 S. Karger AG, Basel
Xiaokang Wang Department of Pharmacy, Shenzhen Longhua District Central Hospital No. 187 Western Guanlan Avenue Shenzhen 518110 (China) kangtae.wang @ yahoo.com
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Keywords Voriconazole · E308G · Febrile neutropenia · Genetic · Adverse effect
Introduction
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Pharmacology DOI: 10.1159/000510327
N F
F F
N
CYPs/FMOs
N N
F
F F
N
Voriconazole
N
N
N+ O–
Voriconazole N-oxide
Fig. 1. VRC liver metabolic pathway and its metabolites. CYPs and FMOs are the main metabolic enzymes of VRC in the process of metabolism. CYPs, cytochrome P450s; FMOs, flavin-containing monooxygenase enzymes; VRC, voriconazole.
nificant correlation between plasma disposition of VRC and the incidence of adverse reactions [15]. When the clinical dosage is the same, the plasma disposal ability of VRC is determined by the pharmacokinetic characteristics of specific patients. The pharmacokinetics of VRC shows a large variability that depends on drug-drug interactions, inflammation, and drug metabolic enzyme gene polymorphism [16]. Therefore, according to the above paragraph, interindividual variability in the expression of FMO3 may affect drugs and xenobiotics in the liver. Early clinical reports have shown that many polymorphisms of FMO3, especially those at the E158K and E308G loci, lead to amino acid substitution that changes the affinity for specific substrates, thus resulting in individual differences in therapy efficacy and safety of VRC [17, 18]. From the research over the past decade, the main gene frequencies of the Han population are E158K (0.229), V257M (0.203), and E308G (0.148) [19]. Studying which variation of the FMO3 gene might affect the ability of individuals to deal with the variety of VRC products that are substrates for FMO3 is of great need. Materials and Methods Study Population and Schedule This observational, single-center, and retrospective study was conducted from January, 2016, to December, 2019, at the Shenzhen Longhua District Central Hospital. All adult patients were tested for CYP2C19 genotypes before grouping, and those who received chemotherapy for either hematological or solid malignancies were screened for enrollment. Of these patients who fulfilled all of the following criteria for both clinical and laboratory diagnoses of FN were included in this study. FN was defined as a neutrophil count 40 IU L−1), and ALT (>50 IU L−1) were evaluated for diagnosing hepatotoxicity during the VRC treatment. Serum potassium concentration (38°C for >1 h [12]. The course of oral treatment with VRC lasts at least 5 days, and each patient is given a dose strictly in accordance with the drug instructions, twice daily. The exclusion criteria were as follows: (1) patients who were under 16 years of age, (2) patients who received a combination of CYP2C19 or CYP3A4 potent modulators (including rifampicin, ritonavir, or carbamazepine, a long-acting barbiturate, or a macrolide antibiotic), (3) patients with hypokalemia (serum potassium 34.2 μmol L−1), (6) patients with a chronic active inflammatory disease (C-reactive protein >5 mg dL−1), and (7) patients with poor compliance with respect to their medications based on electronic medical records. Blood samples (2 mL) were collected for the first time before administration on or after 5 days after the start of VRC therapy.
Table 1. Clinical features and demographics of patients with FN
Variable
Value for characteristica WT
Demographic data Age, years 48 (26–85) Sex, male 34 (52) BMI 22.05 (17.6–28.4) Underlying condition Hematological malignancy 45 (68) Solid-organ transplantation 3 (4.5) Abdominal surgery 1 (1.5) Chronic liver disease 3 (4.5) Other condition 5 (7.5) None 9 (14) Oral VRC therapy 66 VRC daily dose, mg day−1 200 (200–400) Duration of therapy, days 20 (7–45)
E158K
E308G
V257M
49 (27–82) 15 (45) 22.3 (19.6–26.4)
47 (24–80) 16 (47) 21.45 (18.5–25.9)
48 (28–82) 16 (50) 21.3 (17.6–24.5)
24 (73) 2 (6.1) 0 1 (3) 2 (6.1) 4 (11.8) 33 200 (200–400) 20.5 (10–46)
26 (76.5) 2 (6) 0 2 (6) 1 (5.5) 2 (6) 34 200 (200–400) 21 (12–48)
23 (72) 4 (12.5) 1 (3.1) 3 (9.3) 0 1 (3.1) 32 200 (200–400) 21.5 (10–45)
p = 0.0005
3
2
1
0
WT (n = 15)
E158K E308G (n = 10) (n = 6) Genotypes
V257M (n = 7)
Fig. 3. FMO3 polymorphisms on VRC trough concentrations adjusted on the dose (VRC Cmin/D). Influence of FMO3 genotypes on VRC Cmin/D ratio obtained during VRC oral treatment. Data are presented as IQR (boxes), data range (whiskers), and median (horizontal line). Significant p value was obtained by the t test. Data are expressed as mean ± SD. ***p < 0.001 versus the WT group. VRC, voriconazole; WT, wide type of FMO3; IQR, interquartile range.
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Pharmacology DOI: 10.1159/000510327
Results
Patient Characteristics The study selection procedure and grouping are shown in Figure 2. Patients diagnosed with neutropenia were classified by CYP2C19 genotypes (online suppl. Table 2). We identified 365 potentially relevant records through medical records. In accordance with the screening of patient wishes and experimental inclusion criteria, 191 patients with nonintermediate metabolic phenotypes were excluded and 165 patients with intermediate metabolites were left for subject evaluation. A total of 165 patients were treated with oral VRC therapy. These patients were grouped according to FMO3 genotypes, and the following table was obtained (online suppl. Table 3). All the patients were given VRC tablets orally, and other clinical and demographic features of these patients are summarized in Table 1. Influence of FMO3 Polymorphisms on Plasma VRC Trough Concentrations During the oral treatment with VRC, when patients have serious adverse reactions such as diplopia, the blood concentration will be monitored in time to guide the dose adjustment treatment. In this study, 38 patients had severe adverse reactions at the initial stage of treatment, and their serum concentrations of VRC were monitored. The influence of FMO3 polymorphisms was studied on the Wang/Zhao/Wen/Liao/Luo
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Plasma VRC Cmin/D, 103 L–1
4
Color version available online
FN, febrile neutropenia; VRC, voriconazole; WT, wide type of FMO3; IQR, interquartile range. a Data are expressed as median (IQR) or n (%).
Total bilirubin concentration, µmol L–1
4
3
2
1
a
WT (n = 66)
Aspartate aminotransferase, IU L–1
100
80
E158K E308G (n = 33) (n = 34) Genotypes
V257M (n = 32)
b
40
20
E158K E308G (n = 33) (n = 34) Genotypes
WT (n = 66)
E158K E308G (n = 33) (n = 34) Genotypes
V257M (n = 32)
WT (n = 66)
E158K E308G (n = 33) (n = 34) Genotypes
V257M (n = 32)
80
p = 0.047
WT (n = 66)
50
0
p = 0.03
60
0
p = 0.049
100
V257M (n = 32)
60
40
20
0
d
Fig. 4. Clinical and genetic characteristics of the patients with VRC-induced abnormal serum parameters. Minimum serum potassium concentration and maximum TB concentration of each patient were collected from medical records. a Minimum serum potassium concentration was compared among different FMO3 genotypes. b Maximum TB concentration was compared among different FMO3 genotypes. c, d Influence of FMO3 genotypes on the AST and ALT levels. Data are presented as IQR (boxes), data
range (whiskers), and median (horizontal line). Significant p value was obtained by the t test and is shown above. Standard serum potassium concentration: 3.5–5.5 mmol L−1, standard TB concentration: 1.7–17.1 μmol L−1, standard serum AST level: 13–35 U L−1, and standard serum ALT level: 7–40 U L−1. TB, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IQR, interquartile range; WT, wide type of FMO3.
VRC Cmin adjusted on VRC dose (VRC Cmin/D) to overcome the influence of VRC dose. After oral administration, the median VRC Cmin/D was 2.23 (103 L−1) in the wide type of FMO3 (WT) group, 2.53 (103 L−1) in the
E158K group, 2.90 (103 L−1) in the E308G group, and 2.49 (103 L−1) in the V257M group. The plasma VRC Cmin/D in the E308G group was significantly higher than that in the WT group (p = 0.0005), as shown in Figure 3.
FMO3 Variants in Voriconazole Metabolism and Adverse Reactions
Pharmacology DOI: 10.1159/000510327
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0
c
150
p = 0.028
Alanine aminotransferase, IU L–1
Serum potassium concentration, mmol L–1
5
p = 0.03 p = 0.04
60
p = 0.04
20 0
Atopic dermatitis
Influence of FMO3 Genotypes on Clinical Response to VRC Therapy Unlike blood biochemical indicators, the clinical adverse reactions that patients complain about are usually reflected in the medical records. The study collected the medical records of these 165 patients, grouped according to FMO genotypes, and obtained the percentage of patients with adverse reaction symptoms as shown in Figure 5. Pharmacology DOI: 10.1159/000510327
p = 0.04
40
Influence of FMO3 Genotypes on Serum Parameters Among the patients who took VRC orally, there were 15 patients with hypokalemia, and the distribution of serum potassium levels in each group is shown in Figure 4a. The serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028). An abnormal increase in TB occurred in 38 patients, and the distribution of blood TB level in each group is shown in Figure 4b. The abnormal increase in the TB level in the FMO3 E308G genotype group was more significant than that in the WT group (p = 0.049). At the same time, the FMO3 E308G genotype group and E158K genotype group were more likely to have an abnormal AST level. As shown in Figure 4c, there were 27 patients with an abnormal increase in the AST level. Compared with the WT group, the AST level in the E308G genotype group increased significantly (p = 0.03) and the AST level in the E158K genotype group increased significantly (p = 0.047). The level of ALT in each group is also shown in Figure 4d. Compared with the FMO3 WT group, E158K, E308G, and V257M genotype groups also had abnormal growth in different degrees, but there were no significant differences.
6
p = 0.03
Peripheral edema
Headache
Diarrhea
Visual impairment
Atopic dermatitis and visual impairment are common adverse reactions of VRC treatment. In this study, the patients with these adverse reactions were analyzed, in which the incidence of the FMO3 E308G genotype group was 67 and 75%, respectively, compared with the WT genotype group, where the incidence rate was significantly different (p = 0.03). Similarly, the incidences of peripheral edema, headache, and diarrhea in the E308G group were 57, 50, and 60%, respectively, which were significantly different from those in the WT group (p = 0.04). Discussion
In the present study, after the determination of the CYP2C19 metabolic phenotype and FMO3 genotype in all patients, we conducted a statistical analysis mainly on 165 patients with adverse reactions. There was no difference in patients’ age, underlying diseases, genotypes, and average VRC dose between different genders. The metabolic phenotype of CYP2C19 in 165 patients was the same as IM, but there were significant individual differences in FMO3 genotypes. Among these individuals, patients with genotype E308G had a higher risk of adverse reactions than patients with other FMO3 genotypes (WT/E158K/V257M). The FMO3 E308G genotype leads to the increase of plasma VRC Cmin/D. It is suggested that the FMO3 E308G genotype with lower metabolic activity can increase the plasma concentration of VRC, and thus, the FMO3 genotype may play a novel role in altering the adverse reactions of VRC. According to the FDA-approved VRC instructions (Vfend® Tablets; Ascoli Piceno, Italy), there is a wide Wang/Zhao/Wen/Liao/Luo
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Fig. 5. FMO3 genotypes and clinical response to VRC therapy. The incidence of major adverse reactions in patients with different genotypes during the treatment of voriconazole was expressed as percentage. Statistical analysis was carried out by the χ2 test or Fisher’s exact test. Significant p values are displayed above the comparison bar. VRC, voriconazole; WT, wide type of FMO3.
Incidence, %
80
■ WT ■ E158K ■ E308G ■ V257M
Color version available online
100
as patients with neutropenia, stem cell transplantation, and other immunodeficient diseases. Therefore, adverse reactions caused by VRC, such as visual adverse events, headache, diarrhea, and liver function [27], are important parameters for individualized treatment of patients with different genotypes. As expected, abnormalities in the liver function test (TB/AST/ALT) are associated with the use of VRC, which is consistent with the results reported in previous studies [28]. The results of the present study showed that the number of patients with an abnormal increase in AST was 26 (15.8%), and the total incidence of clinically significant transaminase abnormalities in patients who participated in the VRC treatment study reported by Pfizer was 12.4%. The data are slightly higher (Pfizer; data on file), which may be due to the small sample size or ethnic reasons in this study. According to the meta-analysis, there is no correlation between CYP2C19 phenotype, hepatotoxicity, and neurotoxicity [29]. There are only few clinical reports about the effect of FMO3 genotype on the incidence of adverse reactions to VRC. This study suggests that FMO3 genotypes in patients with neutropenia may affect the adverse reactions of VRC by changing plasma exposure. According to the results of the present study, it is found that FMO3 genotyping may help patients use VRC more safely. The main advantage of this study is evaluation of the safety of FMO3 genotypes in VRC treatment of FN with the same phenotype of CYP2C19. To our knowledge, this study is the first to report the effect of the FMO3 E308G genotype on the pharmacokinetics and adverse reactions of VRC in patients with FN. However, our study also has some limitations. First, as more and more studies have shown that severe inflammation can also affect VRC trough concentration [16, 30], CRP or IL-6 concentration can also be used as an important influencing factor. In this study, we excluded patients with chronic underlying inflammatory diseases, resulting in an insufficient sample size in patients with significant inflammation after prophylactic and empirical use of VRC, and failed to analyze the correlation between CRP or IL-6 and VRC trough concentration in patients with FN. Second, although we have tried our best to make the sample size sufficient and the research methods rigorous, as a single disease (FN) and single observation control study, the adverse reactions associated with FMO3 gene polymorphism and other diseases are limited. Therefore, our findings need to be validated in other diseases and multicenter clinical cohorts. Although these limitations remain, the present study is paving the way to a better understanding of VRC and adverse reactions in disease states (e.g., FN).
FMO3 Variants in Voriconazole Metabolism and Adverse Reactions
Pharmacology DOI: 10.1159/000510327
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range of intraindividual/interindividual variations in VRC plasma concentrations in healthy subjects. Previous studies have mainly reported the genetic polymorphism of CYP2C19 enzyme and the effects of nongenetic factors (age, liver disease, and drug interaction) on this variation, but they still do not explain all individual differences [20, 21], especially in unhealthy subjects [22]. Nowadays, more and more researchers focus on the metabolic pathway of VRC and study the polymorphism of the FMO3 gene in order to further find out the reasons for the individual differences in therapy efficacy and safety of VRC in the state of disease [23]. Since FMO3 SNPs may be involved in the nitrogen oxygenation of some amines, including VRC, it is necessary to identify the SNPs in the FMO3 gene of patients with disease and to study the effects of different genotypes on the activity of FMO3 in patients. Some mutations in FMO3 can enhance or weaken its translation ability, and thus increase or decrease the content of FMO3 in the body, make the substrate metabolism of FMO3 abnormal, and affect the efficacy or adverse drug reactions [24]. The study on the relationship between itopride and FMO3 gene polymorphism showed that the combined mutation of FMO3 E158K and E308G could decrease the activity of FMO3, weaken the metabolism of itopride, and significantly increase the blood concentration of itopride [25]. Yamada et al. [26] reported that E158K and E308G mutations in the FMO3 gene can increase the metabolic activity of FMO3, decrease the plasma concentration of VRC, and change the plasma exposure of VRC. The limitation of Yamada et al.’s study [26] is that it aimed at subjects with different phenotypes of CYP2C19. Different phenotypes of CYP2C19 still have a certain impact on the safety of VRC therapy. With the development of precision therapy, the detection of gene polymorphism is widely used in different diseases and drug treatments. Four polymorphisms in exons 4, 6, and 7 of the FM03 gene: c.G472A (p.E158K), c.G769A (p.V257M), and c. A923G (p.E308G), were detected by restriction fragment length polymorphism. Therefore, the method of detecting the FMO3 genotype in this study is the same as that commonly used in molecular clinical diagnosis and can be used as a routine method to predict whether patients will have serious side effects after VRC treatment. Hepatotoxicity and optic neurotoxicity restrict the timely use of antifungal drugs and cause fatal fungal infections to high-risk populations. Adverse drug reactions are an important indicator of preventive treatment; individualized medicine according to patients’ genotypes can not only help avoid adverse drug reactions but also help fight against fungal infections in high-risk groups, such
Conflict of Interest Statement
Conclusion
This is the first study to report that the mutation of FMO3 E308G can decrease the activity of FMO3 enzyme and weaken the metabolic ability of VRC, which may increase the blood concentration of VRC or may lead to adverse reactions in FN.
The authors declare that they have no conflicts of interest to disclose.
Funding Sources This study was funded by Shenzhen Longhua District Science and Technology Innovation Fund Projects (No. 2017032) and a research fund for the instructional project funded by the Wuhan Municipal Health Commission (No. WX18Z30).
Acknowledgements The authors would like to thank Jianghong Liu for her feedback on an earlier draft of this manuscript. The authors would also like to acknowledge the support of students at the Guangdong Medical University for their collaborative effort during data collection.
Statement of Ethics This study was conducted in accordance with the principles of Declaration of Helsinki, and it was approved by the review board and Ethics Committee of Shenzhen Longhua District Central Hospital. All enrolled patients received information about the scientific aim of the study, and each patient signed an informed consent form.
Author Contributions Participated in research design: Wang and Wen; conducted experiments: Wang, Zhao, Liao, and Luo; performed data analysis: Wang and Wen; and wrote or contributed to the writing of the manuscript: Wang and Wen. All authors revised and approved the manuscript.
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Received: May 28, 2020 Accepted: July 20, 2020 Published online: September 30, 2020
Predictive Value of FMO3 Variants on Plasma Disposition and Adverse Reactions of Oral Voriconazole in Febrile Neutropenia Xiaokang Wang a Jingjing Zhao b Ting Wen c Xueyi Liao a Bin Luo b
aDepartment
of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China; bDepartment of Pharmacy, Guangdong Women and Children Hospital, Guangzhou, China; cDepartment of Pharmacology, Wuhan Mental Health Center Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
Abstract Background and Objectives: With the increasing number of patients with febrile neutropenia (FN), voriconazole (VRC) has been widely used in hospitals for first-line treatment of FN. The study was designed for evaluating the influence of FMO3 mutation on the plasma disposition and adverse reactions of VRC in FN. Materials and Methods: A single-center observational study was conducted in the inpatient ward for 4 years. The genotypes of FMO3 and cytochrome P450 (CYP) 2C19 were detected by PCR-restriction fragment length polymorphism. Patients with neutropenia were screened according to the CYP2C19 metabolic phenotype and other inclusion criteria. Five days after empirical administration of VRC, blood concentrations of VRC and nitrogen oxides in patients’ blood were determined by liquid chromatographyelectrospray tandem mass spectrometry (LC-ESI MS/MS). Serum parameters and clinical adverse reaction symptoms in the medical records were collected and statistically analyzed. Results: A total of 165 patients with neutropenia with
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© 2020 S. Karger AG, Basel
the intermediate metabolic phenotype of CYP2C19 were screened. At the initial stage of oral VRC treatment, patients with the FMO3 E308G genotype had a poorer plasma disposal ability to VRC than those with the wide type of FMO3 (WT) genotype (p = 0.0005). Moreover, patients with the FMO3 E308G genotype were more likely to have adverse drug reactions and abnormal serum parameters after receiving VRC treatment. For example, the serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028), the abnormal level of total bilirubin in the FMO3 E308G genotype group was significantly higher than that in the WT group (p = 0.049), and the aspartate aminotransferase level in the E308G group was significantly higher than that in the WT group (p = 0.05). The incidence of atopic dermatitis and visual impairment in the FMO3 E308G genotype group was 67 and 75%, respectively, and the incidences of peripheral neuroedema, headache, and diarrhea were 57, 50, and 60%, respectively, which were significantly different from those in the WT group. Conclusion: FMO3 E308G reduces the activity of the FMO3 enzyme by decreasing the metabolic ability of VRC, which increases the plasma concentration of VRC and may also lead to adverse reactions in patients with FN. © 2020 S. Karger AG, Basel
Xiaokang Wang Department of Pharmacy, Shenzhen Longhua District Central Hospital No. 187 Western Guanlan Avenue Shenzhen 518110 (China) kangtae.wang @ yahoo.com
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Keywords Voriconazole · E308G · Febrile neutropenia · Genetic · Adverse effect
Introduction
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Pharmacology DOI: 10.1159/000510327
N F
F F
N
CYPs/FMOs
N N
F
F F
N
Voriconazole
N
N
N+ O–
Voriconazole N-oxide
Fig. 1. VRC liver metabolic pathway and its metabolites. CYPs and FMOs are the main metabolic enzymes of VRC in the process of metabolism. CYPs, cytochrome P450s; FMOs, flavin-containing monooxygenase enzymes; VRC, voriconazole.
nificant correlation between plasma disposition of VRC and the incidence of adverse reactions [15]. When the clinical dosage is the same, the plasma disposal ability of VRC is determined by the pharmacokinetic characteristics of specific patients. The pharmacokinetics of VRC shows a large variability that depends on drug-drug interactions, inflammation, and drug metabolic enzyme gene polymorphism [16]. Therefore, according to the above paragraph, interindividual variability in the expression of FMO3 may affect drugs and xenobiotics in the liver. Early clinical reports have shown that many polymorphisms of FMO3, especially those at the E158K and E308G loci, lead to amino acid substitution that changes the affinity for specific substrates, thus resulting in individual differences in therapy efficacy and safety of VRC [17, 18]. From the research over the past decade, the main gene frequencies of the Han population are E158K (0.229), V257M (0.203), and E308G (0.148) [19]. Studying which variation of the FMO3 gene might affect the ability of individuals to deal with the variety of VRC products that are substrates for FMO3 is of great need. Materials and Methods Study Population and Schedule This observational, single-center, and retrospective study was conducted from January, 2016, to December, 2019, at the Shenzhen Longhua District Central Hospital. All adult patients were tested for CYP2C19 genotypes before grouping, and those who received chemotherapy for either hematological or solid malignancies were screened for enrollment. Of these patients who fulfilled all of the following criteria for both clinical and laboratory diagnoses of FN were included in this study. FN was defined as a neutrophil count 40 IU L−1), and ALT (>50 IU L−1) were evaluated for diagnosing hepatotoxicity during the VRC treatment. Serum potassium concentration (38°C for >1 h [12]. The course of oral treatment with VRC lasts at least 5 days, and each patient is given a dose strictly in accordance with the drug instructions, twice daily. The exclusion criteria were as follows: (1) patients who were under 16 years of age, (2) patients who received a combination of CYP2C19 or CYP3A4 potent modulators (including rifampicin, ritonavir, or carbamazepine, a long-acting barbiturate, or a macrolide antibiotic), (3) patients with hypokalemia (serum potassium 34.2 μmol L−1), (6) patients with a chronic active inflammatory disease (C-reactive protein >5 mg dL−1), and (7) patients with poor compliance with respect to their medications based on electronic medical records. Blood samples (2 mL) were collected for the first time before administration on or after 5 days after the start of VRC therapy.
Table 1. Clinical features and demographics of patients with FN
Variable
Value for characteristica WT
Demographic data Age, years 48 (26–85) Sex, male 34 (52) BMI 22.05 (17.6–28.4) Underlying condition Hematological malignancy 45 (68) Solid-organ transplantation 3 (4.5) Abdominal surgery 1 (1.5) Chronic liver disease 3 (4.5) Other condition 5 (7.5) None 9 (14) Oral VRC therapy 66 VRC daily dose, mg day−1 200 (200–400) Duration of therapy, days 20 (7–45)
E158K
E308G
V257M
49 (27–82) 15 (45) 22.3 (19.6–26.4)
47 (24–80) 16 (47) 21.45 (18.5–25.9)
48 (28–82) 16 (50) 21.3 (17.6–24.5)
24 (73) 2 (6.1) 0 1 (3) 2 (6.1) 4 (11.8) 33 200 (200–400) 20.5 (10–46)
26 (76.5) 2 (6) 0 2 (6) 1 (5.5) 2 (6) 34 200 (200–400) 21 (12–48)
23 (72) 4 (12.5) 1 (3.1) 3 (9.3) 0 1 (3.1) 32 200 (200–400) 21.5 (10–45)
p = 0.0005
3
2
1
0
WT (n = 15)
E158K E308G (n = 10) (n = 6) Genotypes
V257M (n = 7)
Fig. 3. FMO3 polymorphisms on VRC trough concentrations adjusted on the dose (VRC Cmin/D). Influence of FMO3 genotypes on VRC Cmin/D ratio obtained during VRC oral treatment. Data are presented as IQR (boxes), data range (whiskers), and median (horizontal line). Significant p value was obtained by the t test. Data are expressed as mean ± SD. ***p < 0.001 versus the WT group. VRC, voriconazole; WT, wide type of FMO3; IQR, interquartile range.
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Pharmacology DOI: 10.1159/000510327
Results
Patient Characteristics The study selection procedure and grouping are shown in Figure 2. Patients diagnosed with neutropenia were classified by CYP2C19 genotypes (online suppl. Table 2). We identified 365 potentially relevant records through medical records. In accordance with the screening of patient wishes and experimental inclusion criteria, 191 patients with nonintermediate metabolic phenotypes were excluded and 165 patients with intermediate metabolites were left for subject evaluation. A total of 165 patients were treated with oral VRC therapy. These patients were grouped according to FMO3 genotypes, and the following table was obtained (online suppl. Table 3). All the patients were given VRC tablets orally, and other clinical and demographic features of these patients are summarized in Table 1. Influence of FMO3 Polymorphisms on Plasma VRC Trough Concentrations During the oral treatment with VRC, when patients have serious adverse reactions such as diplopia, the blood concentration will be monitored in time to guide the dose adjustment treatment. In this study, 38 patients had severe adverse reactions at the initial stage of treatment, and their serum concentrations of VRC were monitored. The influence of FMO3 polymorphisms was studied on the Wang/Zhao/Wen/Liao/Luo
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Plasma VRC Cmin/D, 103 L–1
4
Color version available online
FN, febrile neutropenia; VRC, voriconazole; WT, wide type of FMO3; IQR, interquartile range. a Data are expressed as median (IQR) or n (%).
Total bilirubin concentration, µmol L–1
4
3
2
1
a
WT (n = 66)
Aspartate aminotransferase, IU L–1
100
80
E158K E308G (n = 33) (n = 34) Genotypes
V257M (n = 32)
b
40
20
E158K E308G (n = 33) (n = 34) Genotypes
WT (n = 66)
E158K E308G (n = 33) (n = 34) Genotypes
V257M (n = 32)
WT (n = 66)
E158K E308G (n = 33) (n = 34) Genotypes
V257M (n = 32)
80
p = 0.047
WT (n = 66)
50
0
p = 0.03
60
0
p = 0.049
100
V257M (n = 32)
60
40
20
0
d
Fig. 4. Clinical and genetic characteristics of the patients with VRC-induced abnormal serum parameters. Minimum serum potassium concentration and maximum TB concentration of each patient were collected from medical records. a Minimum serum potassium concentration was compared among different FMO3 genotypes. b Maximum TB concentration was compared among different FMO3 genotypes. c, d Influence of FMO3 genotypes on the AST and ALT levels. Data are presented as IQR (boxes), data
range (whiskers), and median (horizontal line). Significant p value was obtained by the t test and is shown above. Standard serum potassium concentration: 3.5–5.5 mmol L−1, standard TB concentration: 1.7–17.1 μmol L−1, standard serum AST level: 13–35 U L−1, and standard serum ALT level: 7–40 U L−1. TB, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IQR, interquartile range; WT, wide type of FMO3.
VRC Cmin adjusted on VRC dose (VRC Cmin/D) to overcome the influence of VRC dose. After oral administration, the median VRC Cmin/D was 2.23 (103 L−1) in the wide type of FMO3 (WT) group, 2.53 (103 L−1) in the
E158K group, 2.90 (103 L−1) in the E308G group, and 2.49 (103 L−1) in the V257M group. The plasma VRC Cmin/D in the E308G group was significantly higher than that in the WT group (p = 0.0005), as shown in Figure 3.
FMO3 Variants in Voriconazole Metabolism and Adverse Reactions
Pharmacology DOI: 10.1159/000510327
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0
c
150
p = 0.028
Alanine aminotransferase, IU L–1
Serum potassium concentration, mmol L–1
5
p = 0.03 p = 0.04
60
p = 0.04
20 0
Atopic dermatitis
Influence of FMO3 Genotypes on Clinical Response to VRC Therapy Unlike blood biochemical indicators, the clinical adverse reactions that patients complain about are usually reflected in the medical records. The study collected the medical records of these 165 patients, grouped according to FMO genotypes, and obtained the percentage of patients with adverse reaction symptoms as shown in Figure 5. Pharmacology DOI: 10.1159/000510327
p = 0.04
40
Influence of FMO3 Genotypes on Serum Parameters Among the patients who took VRC orally, there were 15 patients with hypokalemia, and the distribution of serum potassium levels in each group is shown in Figure 4a. The serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028). An abnormal increase in TB occurred in 38 patients, and the distribution of blood TB level in each group is shown in Figure 4b. The abnormal increase in the TB level in the FMO3 E308G genotype group was more significant than that in the WT group (p = 0.049). At the same time, the FMO3 E308G genotype group and E158K genotype group were more likely to have an abnormal AST level. As shown in Figure 4c, there were 27 patients with an abnormal increase in the AST level. Compared with the WT group, the AST level in the E308G genotype group increased significantly (p = 0.03) and the AST level in the E158K genotype group increased significantly (p = 0.047). The level of ALT in each group is also shown in Figure 4d. Compared with the FMO3 WT group, E158K, E308G, and V257M genotype groups also had abnormal growth in different degrees, but there were no significant differences.
6
p = 0.03
Peripheral edema
Headache
Diarrhea
Visual impairment
Atopic dermatitis and visual impairment are common adverse reactions of VRC treatment. In this study, the patients with these adverse reactions were analyzed, in which the incidence of the FMO3 E308G genotype group was 67 and 75%, respectively, compared with the WT genotype group, where the incidence rate was significantly different (p = 0.03). Similarly, the incidences of peripheral edema, headache, and diarrhea in the E308G group were 57, 50, and 60%, respectively, which were significantly different from those in the WT group (p = 0.04). Discussion
In the present study, after the determination of the CYP2C19 metabolic phenotype and FMO3 genotype in all patients, we conducted a statistical analysis mainly on 165 patients with adverse reactions. There was no difference in patients’ age, underlying diseases, genotypes, and average VRC dose between different genders. The metabolic phenotype of CYP2C19 in 165 patients was the same as IM, but there were significant individual differences in FMO3 genotypes. Among these individuals, patients with genotype E308G had a higher risk of adverse reactions than patients with other FMO3 genotypes (WT/E158K/V257M). The FMO3 E308G genotype leads to the increase of plasma VRC Cmin/D. It is suggested that the FMO3 E308G genotype with lower metabolic activity can increase the plasma concentration of VRC, and thus, the FMO3 genotype may play a novel role in altering the adverse reactions of VRC. According to the FDA-approved VRC instructions (Vfend® Tablets; Ascoli Piceno, Italy), there is a wide Wang/Zhao/Wen/Liao/Luo
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Fig. 5. FMO3 genotypes and clinical response to VRC therapy. The incidence of major adverse reactions in patients with different genotypes during the treatment of voriconazole was expressed as percentage. Statistical analysis was carried out by the χ2 test or Fisher’s exact test. Significant p values are displayed above the comparison bar. VRC, voriconazole; WT, wide type of FMO3.
Incidence, %
80
■ WT ■ E158K ■ E308G ■ V257M
Color version available online
100
as patients with neutropenia, stem cell transplantation, and other immunodeficient diseases. Therefore, adverse reactions caused by VRC, such as visual adverse events, headache, diarrhea, and liver function [27], are important parameters for individualized treatment of patients with different genotypes. As expected, abnormalities in the liver function test (TB/AST/ALT) are associated with the use of VRC, which is consistent with the results reported in previous studies [28]. The results of the present study showed that the number of patients with an abnormal increase in AST was 26 (15.8%), and the total incidence of clinically significant transaminase abnormalities in patients who participated in the VRC treatment study reported by Pfizer was 12.4%. The data are slightly higher (Pfizer; data on file), which may be due to the small sample size or ethnic reasons in this study. According to the meta-analysis, there is no correlation between CYP2C19 phenotype, hepatotoxicity, and neurotoxicity [29]. There are only few clinical reports about the effect of FMO3 genotype on the incidence of adverse reactions to VRC. This study suggests that FMO3 genotypes in patients with neutropenia may affect the adverse reactions of VRC by changing plasma exposure. According to the results of the present study, it is found that FMO3 genotyping may help patients use VRC more safely. The main advantage of this study is evaluation of the safety of FMO3 genotypes in VRC treatment of FN with the same phenotype of CYP2C19. To our knowledge, this study is the first to report the effect of the FMO3 E308G genotype on the pharmacokinetics and adverse reactions of VRC in patients with FN. However, our study also has some limitations. First, as more and more studies have shown that severe inflammation can also affect VRC trough concentration [16, 30], CRP or IL-6 concentration can also be used as an important influencing factor. In this study, we excluded patients with chronic underlying inflammatory diseases, resulting in an insufficient sample size in patients with significant inflammation after prophylactic and empirical use of VRC, and failed to analyze the correlation between CRP or IL-6 and VRC trough concentration in patients with FN. Second, although we have tried our best to make the sample size sufficient and the research methods rigorous, as a single disease (FN) and single observation control study, the adverse reactions associated with FMO3 gene polymorphism and other diseases are limited. Therefore, our findings need to be validated in other diseases and multicenter clinical cohorts. Although these limitations remain, the present study is paving the way to a better understanding of VRC and adverse reactions in disease states (e.g., FN).
FMO3 Variants in Voriconazole Metabolism and Adverse Reactions
Pharmacology DOI: 10.1159/000510327
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range of intraindividual/interindividual variations in VRC plasma concentrations in healthy subjects. Previous studies have mainly reported the genetic polymorphism of CYP2C19 enzyme and the effects of nongenetic factors (age, liver disease, and drug interaction) on this variation, but they still do not explain all individual differences [20, 21], especially in unhealthy subjects [22]. Nowadays, more and more researchers focus on the metabolic pathway of VRC and study the polymorphism of the FMO3 gene in order to further find out the reasons for the individual differences in therapy efficacy and safety of VRC in the state of disease [23]. Since FMO3 SNPs may be involved in the nitrogen oxygenation of some amines, including VRC, it is necessary to identify the SNPs in the FMO3 gene of patients with disease and to study the effects of different genotypes on the activity of FMO3 in patients. Some mutations in FMO3 can enhance or weaken its translation ability, and thus increase or decrease the content of FMO3 in the body, make the substrate metabolism of FMO3 abnormal, and affect the efficacy or adverse drug reactions [24]. The study on the relationship between itopride and FMO3 gene polymorphism showed that the combined mutation of FMO3 E158K and E308G could decrease the activity of FMO3, weaken the metabolism of itopride, and significantly increase the blood concentration of itopride [25]. Yamada et al. [26] reported that E158K and E308G mutations in the FMO3 gene can increase the metabolic activity of FMO3, decrease the plasma concentration of VRC, and change the plasma exposure of VRC. The limitation of Yamada et al.’s study [26] is that it aimed at subjects with different phenotypes of CYP2C19. Different phenotypes of CYP2C19 still have a certain impact on the safety of VRC therapy. With the development of precision therapy, the detection of gene polymorphism is widely used in different diseases and drug treatments. Four polymorphisms in exons 4, 6, and 7 of the FM03 gene: c.G472A (p.E158K), c.G769A (p.V257M), and c. A923G (p.E308G), were detected by restriction fragment length polymorphism. Therefore, the method of detecting the FMO3 genotype in this study is the same as that commonly used in molecular clinical diagnosis and can be used as a routine method to predict whether patients will have serious side effects after VRC treatment. Hepatotoxicity and optic neurotoxicity restrict the timely use of antifungal drugs and cause fatal fungal infections to high-risk populations. Adverse drug reactions are an important indicator of preventive treatment; individualized medicine according to patients’ genotypes can not only help avoid adverse drug reactions but also help fight against fungal infections in high-risk groups, such
Conflict of Interest Statement
Conclusion
This is the first study to report that the mutation of FMO3 E308G can decrease the activity of FMO3 enzyme and weaken the metabolic ability of VRC, which may increase the blood concentration of VRC or may lead to adverse reactions in FN.
The authors declare that they have no conflicts of interest to disclose.
Funding Sources This study was funded by Shenzhen Longhua District Science and Technology Innovation Fund Projects (No. 2017032) and a research fund for the instructional project funded by the Wuhan Municipal Health Commission (No. WX18Z30).
Acknowledgements The authors would like to thank Jianghong Liu for her feedback on an earlier draft of this manuscript. The authors would also like to acknowledge the support of students at the Guangdong Medical University for their collaborative effort during data collection.
Statement of Ethics This study was conducted in accordance with the principles of Declaration of Helsinki, and it was approved by the review board and Ethics Committee of Shenzhen Longhua District Central Hospital. All enrolled patients received information about the scientific aim of the study, and each patient signed an informed consent form.
Author Contributions Participated in research design: Wang and Wen; conducted experiments: Wang, Zhao, Liao, and Luo; performed data analysis: Wang and Wen; and wrote or contributed to the writing of the manuscript: Wang and Wen. All authors revised and approved the manuscript.
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