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Patient characteristics, invasive fungal infections and genotypes, by CYP2C19 phenotype
Source publication
The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD.
As a single-centre pilot study, 19 consecutive patients with a haematological malign...
Context in source publication
Similar publications
The objective of this study was to determine the economic impact of proactive, CYP2C19 genotype-guided voriconazole prophylaxis in AML.
An Excel-based model was created to project the cost of treating a simulated cohort of severely neutropenic AML patients undergoing antifungal prophylaxis. The model compares (i) standard prophylactic dosing with v...
Citations
... Weiss et al. proposed that CYP2C19 genotype significantly contributed to the high variability observed in VRC PK [46]. Trubiano et al. [47] also suggested that the CYP2C19 genotype could be utilized to predict VRC C trough and toxicity. Many studies suggested using CYP2C19 genotype to guide the initial dosing regimen of VRC [48,49]. ...
... This discrepancy may be attributed to the distinct roles of CYP2C19, CYP3A4, and flavin-containing monooxygenase 3 (FMO-3) in VRC N-oxidation between pediatric patients and adults. Studies have found that the CL of VRC in patients aged 2 to 11 years was nearly three times that of adults [47]. CYP2C19 and FMO-3 exhibited higher metabolic activity in young children, and the downregulation of CYP2C19 isoforms during inflammation had a relatively minor impact on VRC metabolism in younger children. ...
The purpose of this study was to review the literature on the clinical use of voriconazole (VRC) in pediatric patients. MEDLINE, Embase, PubMed, Web of Science, and Cochrane Library were searched from January 1, 2000, to August 15, 2023 for relevant clinical studies on VRC use in pediatric patients. Data were collected based on inclusion and exclusion criteria, and a systematic review was performed on recent research related to the use of VRC in pediatric patients. This systematic review included a total of 35 observational studies among which there were 16 studies investigating factors influencing VRC plasma trough concentrations (C trough ) in pediatric patients, 14 studies exploring VRC maintenance doses required to achieve target range of C trough , and 11 studies focusing on population pharmacokinetic (PPK) research of VRC in pediatric patients. Our study found that the C trough of VRC were influenced by both genetic and non-genetic factors. The optimal dosing of VRC was correlated with age in pediatric patients, and younger children usually required higher VRC doses to achieve target C trough compared to older children. Establishing a PPK model for VRC can assist in achieving more precise individualized dosing in children.
... There is a significant association between CYP2C19 phenotype and voriconazole trough concentrations [8]. About 63% to 80% of rapid (RMs) or ultra-rapid metabolizers (UMs) (*1/*17 or *17/*17 genotypes, respectively) have subtherapeutic voriconazole concentrations with standard prophylaxis dosing, thus placing patients at risk of breakthrough IFIs [9][10][11]. Roughly one-third of White and Black patients are RMs or UMs [8]. ...
CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.
... As the proportion of PMs in Asian populations is higher, a lower maintenance dose may be required to achieve the same plasma concentrations. CYP2C19 phenotypes can be used to guide initial VRC dosing and often explain subtherapeutic concentrations [25]. Significant differences in VRC plasma concentrations were observed among the three CYP2C19 phenotypes in our study. ...
The aim of this study was to evaluate factors that impact on voriconazole (VRC) population pharmacokinetic (PPK) parameters and explore the optimal dosing regimen for different CYP2C19 genotypes in Chinese paediatric patients. PPK analysis was used to identify the factors contributing to the variability in VRC plasma trough concentrations. A total of 210 VRC trough concentrations from 91 paediatric patients were included in the study. The median VRC trough concentration was 1.23 mg/L (range, 0.02 to 8.58 mg/L). At the measurement of all the trough concentrations, the target range (1.0~5.5 mg/L) was achieved in 52.9% of the patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.9% and 6.2% of patients, respectively. VRC trough concentrations were adjusted for dose (Ctrough/D), with normal metabolizers (NMs) and intermediate metabolizers (IMs) having significantly lower levels than poor metabolizers (PMs) (PN-P < 0.001, PI-P = 0.039). A one-compartment model with first-order absorption and elimination was suitable to describe the VRC pharmacokinetic characteristics. The final model of VRC PPK analysis contained CYP2C19 phenotype as a significant covariate for clearance. Dose simulations suggested that a maintenance dose of 9 mg/kg orally or 8 mg/kg intravenously twice daily was appropriate for NMs to achieve the target concentration. A maintenance dose of 9 mg/kg orally or 5 mg/kg intravenously twice daily was appropriate for IMs. Meanwhile, PMs could use lower maintenance dose and an oral dose of 6 mg/kg twice daily or an intravenous dose of 5mg/kg twice daily was appropriate. To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict VRC trough concentrations and guide dose adjustments in Chinese pediatric patients.
... Additionally, guidelines also recommend frequent monitoring of VRC trough concentration in pediatric patients [16]. CYP2C19 phenotypes play a crucial role in guiding the initial VRC dosing [18]. Significant differences in VRC plasma trough concentrations were observed among the three CYP2C19 phenotypes. ...
Purpose
The objective of this study was to evaluate factors influencing voriconazole (VRC) plasma trough concentrations and provide research data for optimizing VRC dosing in Chinese paediatric patients.
Methods
Medical records of inpatients were reviewed retrospectively. Multivariate linear regression analysis was used to identify the factors contributing to the variability of VRC plasma trough concentrations.
Results
A total of 250 VRC plasma trough concentrations from 131 paediatric patients were included in the analysis. The median VRC plasma trough concentration was 1.28 mg·L⁻¹ (range, 0.02 to 9.69 mg·L⁻¹). The target range was achieved in 51.6% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.4% and 8.0% of paediatric patients, respectively. The most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was intermediate metabolizers (IMs) (48.9%), followed by normal metabolizers (NMs) (40.5%) and poor metabolizers (PMs) (10.7%), but no ultrarapid metabolizers (UMs) were observed in our study. VRC plasma trough concentrations adjusted for dose (Cmin/D) were significantly lower in both NMs and IMs compared to PMs (PN-P < 0.001 and PI-P = 0.010, respectively). The dosage of VRC required to achieve the therapeutic range was related to age, with children aged < 6 years needing a significantly higher oral dose of VRC. The oral and intravenous maintenance doses needed to reach the therapeutic range were significantly lower than the recommended maintenance dose (P < 0.001, P < 0.001). Factors such as CYP2C19 polymorphisms, the combination of omeprazole, levels of albumin and alanine aminotransferase, were found to affect VRC exposure and explained some of the variability.
Conclusions
The VRC plasma trough concentration is significantly influenced by the CYP2C19 phenotype. The recommended maintenance dose for pediatric patients may not be appropriate for Chinese patients. To increase the probability of achieving the therapeutic range for VRC plasma trough concentration, the administration of VRC should consider the age of paediatric patients and the presence of CYP2C19 polymorphisms.
... There is a signi cant association between CYP2C19 phenotype and voriconazole trough concentrations (8). About 63-80% of rapid (RMs) or ultra-rapid metabolizers (UMs) (*1/*17 or *17/*17 genotypes, respectively) have subtherapeutic voriconazole concentrations with standard prophylaxis dosing, thus placing patients at risk of breakthrough IFIs (9)(10)(11). Roughly one-third of White and Black patients are RMs or UMs (8). ...
CYP2C19 -guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19 -guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19 -guided voriconazole dosing. Patients were genotyped for ABCB1 , ABCG2 , CYP2C9 , CYP3A4 , CYP3A5 , and the CYP2C haplotype were genotyped. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 , ABCG2 , age, and letermovir use were associated with voriconazole concentrations and may be used to improve voriconazole precision dosing.
... In our study, PMs had signi cantly higher initial plasma concentrations than NMs and IMs, other studies [20][21] also con rmed this in their study. CYP2C19 phenotypes can be used to guide initial voriconazole dosing and often explain subtherapeutic concentrations [22]. [9] found that the plasma concentration of patients aged ≥ 60 years was signi cantly higher than in those < 60 years old, which was similar to our study. ...
Aims
The aim of this study was to evaluate factors that impact on voriconazole trough concentration and explore the optimal dosing regimen of voriconazole for different CYP2C19 genotypes in a Chinese population.
Methods
Medical records of inpatients were reviewed retrospectively. Multivariate linear regression and population pharmacokinetic analysis was used to identify the factors contributing to the variability of voriconazole trough concentrations.
Results
A total of 363 voriconazole trough concentrations from 89 patients were included, with high inter- and intraindividual variability. At the measurement of the first trough concentration, the target range (1.0–5.5 mg·L− 1) was achieved in 68.5% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 28.1% and 3.4% of patients, respectively. In our study, the most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was normal metabolizers (NMs) (46.1%), followed by intermediate metabolizers (IMs) (40.4%) and poor metabolizers (PMs) (13.5%). Initial trough concentrations were adjusted for dose, with NMs and IMs were both significantly lower than PMs (PN−P=0.010 and PI−P=0.048, respectively). The median intravenous maintenance dose to reach a therapeutic range was significantly lower than the recommended intravenous maintenance dose (P = 0.009). Affecting factors in our study such as age, administration routes, CYP2C19 polymorphisms and aspartate transaminase (AST) explained 41.4% of the variability in voriconazole exposure. The final model of voriconazole population pharmacokinetic analysis contained age as a significant covariate for the distribution volume and CYP2C19 phenotype as a significant covariate for the clearance rate. Dose simulations indicated that 300, 250, 150 mg orally twice daily is appropriate for NMs, IMs and PMs to achieve target range, respectively.
Conclusions
To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict voriconazole trough concentrations and guide dose adjustment.
... Recently, we have demonstrated quantitative relations between the CYP2C19 polymorphisms and voriconazole trough concentrations 13 . Accordingly, polymorphisms of the CYP2C19 have been associated with antifungal response and are supposed to predict the variability in clinical response to voriconazole 14 . However, published literatures have not consistently shown an association of CYP2C19 polymorphism with clinical response of voriconazole. ...
... Thirteen studies analyzed the association of CYP2C19 phenotype with the safety outcome of overall adverse events 14 Subgroup analysis revealed that the results in groups treatment and Asians were not significantly changed. However, in the subgroup of Caucasians, there were a limited number of studies (2˜4) and no significant differences were found in all comparisons (Table 4). ...
Aims: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. Methods: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to March 18, 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity and neurotoxicity. Results: A total of 20 studies were included. Intermediate metabolizers (IMs) and Poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) (risk ratio (RR): 1.18, 95% confidence interval (CI): 1.03~1.34, I2=0%, p=0.02; RR: 1.28, 95%CI: 1.06~1.54, I2=0%, p=0.01). PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR: 2.18, 95%CI: 1.35~3.53, I2=0%, p=0.001; RR: 1.80, 95% CI: 1.23~2.64, I2=0%, p=0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR: 1.60, 95%CI: 0.94~2.74, I2=27%, p=0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. Conclusions: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deservers clinical attention.
... In this context, VRC personalized treatment with a priori dose adjustment has already been proposed instead of five days after the initiation of treatment [4]. Such strategies are most frequently based on the cytochrome P450 (CYP) 2C19 genotype [11][12][13][14], as many studies have demonstrated the contribution of CYP2C19 polymorphisms in the variability of VRC trough concentrations (Cmin) [15][16][17][18]. ...
Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.
... The UM patient, on the other hand, remained subtherapeutic despite dose adjustments and finally demonstrated treatment response after being switched to isavuconazole. Trubiano et al. conducted a prospective pilot study in 19 patients and found IM phenotypes were more likely to experience voriconazole side effects (photopsia and hepatotoxicity) which were most likely as a result of higher trough concentrations [38]. High troughs, however, are not consistently associated with hepatotoxicity as observed in a study by Wang et al., using a predominant Asian cohort with larger numbers of IM (n = 62) and PM (n = 17) [37]. ...
Purpose of Review
This review summarizes recent literature for applying pharmacogenomics to antifungal selection and dosing, providing an approach to implementing antifungal pharmacogenomics in clinical practice.
Recent Findings
The Clinical Pharmacogenetics Implementation Consortium published guidelines on CYP2C19 and voriconazole, with recommendations to use alternative antifungals or adjust voriconazole dose with close therapeutic drug monitoring (TDM). Recent studies demonstrate an association between CYP2C19 phenotype and voriconazole levels, clinical outcomes, and adverse events. Additionally, CYP2C19-guided preemptive dose adjustment demonstrated benefit in two prospective studies for prophylaxis. Pharmacokinetic–pharmacodynamic modeling studies have generated proposed voriconazole treatment doses based on CYP2C19 phenotypes, with further validation studies needed.
Summary
Sufficient evidence is available for implementing CYP2C19-guided voriconazole selection and dosing among select patients at risk for invasive fungal infections. The institution needs appropriate infrastructure for pharmacogenomic testing, integration of results in the clinical decision process, with TDM confirmation of goal trough achievement, to integrate antifungal pharmacogenomics into routine clinical care.
... The majority of the cyclosporinerelated pharmacogenetic studies have evaluated polymorphisms in the ABCB1, CYP3A4, and CYP3A5 genes because of their role in cyclosporine disposition [13]. As for voriconazole, it is now established that CYP2C19 is the major determinant of its pharmacokinetic variability [14,15]; yet CYP2C9, CYP3A4, and ABCB1 were also shown to play a role, and hence the potential inhibition of cyclosporine elimination by voriconazole [16]. ...
... Interestingly, in a pharmacogenetic study on Australian patients with hematological malignancies requiring voriconazole treatment for invasive fungal infection, despite the smaller sample size (N = 19), CYP2C19 intermediate metabolizers were associated with higher voriconazole levels and more clinical toxicity when compared to extensive and ultra CYP2C19 metabolizers. Of note that the frequency of the intermediate metabolizer phenotype was higher than the one we found in our sample: 26% vs. 15% [15]. It remains unknown why one subject with the CYP2C19 slow metabolizer phenotype had a lower C/D ratio than the intermediate phenotype. ...
Purpose:
To evaluate polymorphisms in genes of drug metabolizing enzymes and transporters involved in cyclosporine and/or voriconazole disposition among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT).
Methods:
DNA from forty patients was genotyped using the DMETPlus array. The average ratio of cyclosporine concentration/dose (C/D in (ng/mL)/(mg/kg)) per participant's weight was computed using available trough levels and daily doses.
Results:
The C/D cyclosporine ratio was significantly higher when it was administered with voriconazole as compared to when it was administered alone: median: 116.75 vs. 25.40 (ng/mL)/(mg/kg) with and without voriconazole respectively, (P < 0.001). There was also a significant association between the C/D cyclosporine ratio combined with voriconazole and the ABCB1 2677 G > T > A (rs2032582) genetic polymorphism (P = 0.05). In parallel, ABCB1 variant allele carriers had higher creatinine in combination therapy with a median creatinine (mg/dL) of 0.74 vs. 0.56 for variant allele carriers vs. reference; P = 0.003. Interestingly, CYP2C9, CYP2C19, and CYP3A5 extensive metabolizers tended to be associated with lower cyclosporine C/D ratio when combined with voriconazole, but the results were not statistically significant.
Conclusion:
To the best of our knowledge, this is the first pharmacogenetic study on the interaction between voriconazole and cyclosporine in patients undergoing allo-HCT. Results suggest that the ABCB1 2677 G > T > A genetic polymorphism plays a role in this interaction with cyclosporine related nephrotoxicity. Pre-emptive genotyping for this genetic variant may be warranted for cyclosporine dose optimization. Larger studies are needed to potentially show significant associations with more candidate genes such as CYP3A4/5, CYP2C9, and CYP2C19, among others.
