Voriconazole Metabolism, Toxicity, and the Effect of Cytochrome P450 2C19 Genotype

Zonios, Dimitrios I.; Yamazaki, Hiroshi; Murayama, Norie; Natarajan, Ven; Palmore, Tara N.; Childs, Richard W.; Skinner, Jeff; Bennett, John E.

doi:10.1093/infdis/jiu017

Cited by 92 publications

(119 citation statements)

References 20 publications

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“…In the present study, we found that the minor allele frequency of CYP2C9*2 and CYP2C9*3 SNPs in our population was very low, in accordance with that seen in the Chinese Han population through the HapMap database. This can also be interpreted as the *2 and *3 SNPs not affecting the plasma voriconazole concentration in the Chinese population, in accordance with the findings of the three aforementioned studies [13,18,27]. No effect was found for the other SNPs of CYP2C9.…”

Section: Discussionsupporting

confidence: 90%

“…While there are few published controlled clinical trials regarding the influence of different CYP2C9 genotypes on the pharmacokinetics and metabolism of voriconazole, there have been some indications that the CYP2C9 genotype might not be relevant to voriconazole pharmacokinetics. One study found no effect of the CYP2C9 genotype on voriconazole levels [27]. Furthermore, a case report found that the voriconazole pharmacokinetics of a patient who was homozygous for CYP2C9*2 were unchanged [18].…”

Section: Discussionmentioning

confidence: 99%

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Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Sun

Ren

et al. 2014

Eur J Clin Microbiol Infect Dis

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Voriconazole is frequently utilized for the prevention and treatment of invasive fungal infections (IFIs), and is extensively metabolized by the cytochrome P450 (CYP) system. The impact of activity of the genes encoding CYP3A4, CYP3A5, and CYP2C9 on the pharmacokinetics of voriconazole cannot be ignored because, second to CYP2C19, they are the most important enzymes involved in voriconazole metabolism. The influence of genetic polymorphisms in CYP3A4, CYP3A5, and CYP2C9 on the plasma concentrations of voriconazole was evaluated in the present study. The study cohort comprised 158 patients with IFIs in whom 22 single-nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP2C9 were genotyped using the Sequenom MassARRAY RS1000 system, and voriconazole plasma concentrations were measured by high-performance liquid chromatography (HPLC). 40, 91, and 27 patients presented with low (<1 mg/L), normal (1-4 mg/L), and high (>4 mg/L) plasma voriconazole concentrations, respectively. Correlation analysis between polymorphisms and the plasma voriconazole concentration revealed an association between the presence of the rs4646437 T allele and a higher plasma voriconazole concentration [p = 0.033, odds ratio (OR) = 2.832, 95% confidence interval (CI) = 1.086-7.384]. This study has identified a new SNP related to the metabolism of voriconazole, potentially providing novel insight into the influence of CYP3A4 on the pharmacokinetics of this antifungal agent.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Sun

Ren

et al. 2014

Eur J Clin Microbiol Infect Dis

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“…Most reports have been in children, with incidence reported to be as high as 20% [55], and 10.5% in patients aged over 12 years [56]. However, neither study was specific to patients who had received alloHSCT.…”

Section: Adverse Eventsmentioning

confidence: 99%

Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation

Marks

Liu

Slavin

2017

Expert Review of Anti-infective Therapy

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Introduction: Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden. Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients. Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT.ARTICLE HISTORY

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“…At present, the relationship between voriconazole concentrations and toxicity is not well understood [60,121].…”

Section: Safetymentioning

confidence: 99%

“…CYP2C19 represents about 1% and CYP3A4 approximately 30% of the total hepatic complement [182]. To varying degrees, voriconazole is an inhibitor and/or substrate of CYPs 2B6, 2C19, 2C9, and 3A4 [9,164,183,184] with CYP2C19 playing the predominant, but not exclusive role in voriconazole's metabolism [121,185,186]. Genetic variation in CYP2C19 that limits metabolic activity may influence the potential for DDIs [18,58,187].…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections

Job

Olson

Constance

et al. 2016

Expert Review of Anti-infective Therapy

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The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.

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Voriconazole Metabolism, Toxicity, and the Effect of Cytochrome P450 2C19 Genotype

Abstract: CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified.

Cited by 92 publications

References 20 publications

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation

Pharmacodynamic studies of voriconazole: informing the clinical management of invasive fungal infections

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