Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients

Berge, Marion; Guillemain, R.; Trégouët, David‐Alexandre; Amrein, C.; Boussaud, V.; Chevalier, P.; Lillo‐Lelouet, Agnès; Beller, Christine Le; Laurent‐Puig, Pierre; Beaune, Philippe; Billaud, Éliane; Loriot, Marie‐Anne

doi:10.1007/s00228-010-0914-2

Cited by 55 publications

(67 citation statements)

References 34 publications

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“…The drug undergoes extensive metabolism via CYP-3A4, CYP-2C9, and CYP-2C19. CYP-2C19 is a polymorphic genotype that is responsible for much of the wide variation in drug clearance and exposure (193). Voriconazole clearance averages 932 ml/min in ultrarapid metabolizers, 522 ml/min in extensive metabolizers, and 147 ml/min in poor metabolizers (194).…”

Section: Advances In Antifungal Therapy For Coccidioidomycosismentioning

confidence: 99%

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

et al. 2013

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SUMMARY Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii . This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

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Section: Advances In Antifungal Therapy For Coccidioidomycosismentioning

confidence: 99%

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

et al. 2013

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“…On the other hand, voriconazole-related photosensitivity has rarely been reported in CF children or adult patients [2,[6][7]. This high rate of photosensitivity was not in line with the previous reported ratio of 14% in CF children [2], but closer to 40% in lung-transplanted CF adults [6]. A recent Canadian case report raised the question of voriconazole safety as five out of the six CF children treated with voriconazole presented photosensitivity.…”

mentioning

confidence: 79%

“…The occurrence of voriconazole-related photosensitivity was related neither to the length of the treatment nor to the administered dose. Although not assessed in this survey, a relationship with high serum levels appeared unlikely as previously shown [6][7][8]. Lastly, ciprofloxacin, well known to induce photosensitivity, was excluded as an interfering risk factor.…”

mentioning

confidence: 86%

“…Skin eruptions [1] have been described in 0.5 to 5.3% of cases in various phase III trials [4], and recently up to 8.3% in an open study on chronic aspergillosis treatment [5]. On the other hand, voriconazole-related photosensitivity has rarely been reported in CF children or adult patients [2,[6][7]. This high rate of photosensitivity was not in line with the previous reported ratio of 14% in CF children [2], but closer to 40% in lung-transplanted CF adults [6].…”

mentioning

confidence: 99%

“…Voriconazole is metabolised by the human cytochrome P-450 and its isoenzymes, mainly CYP2C19 and to a lesser extent CYP2C9 and CYP3A4, but no relationship has yet been demonstrated between this pathway and photoreactions [1]. Thus, BERGE et al [6] have recently proven that CYP2C19 genotypes influence voriconazole exposure without any impact on the occurrence of AEs [6]. Voriconazole-related skin reactions have been assimilated to retinoid-like sensitivity [3], as retinoid acid and metabolites induced photosensitivity and high serum levels were measured in three out of the five reported adults [5].…”

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confidence: 99%

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High frequency of voriconazole-related phototoxicity in cystic fibrosis patients

Rondeau¹,

Couderc²,

Dominique³

et al. 2012

European Respiratory Journal

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To the Editors:Aspergillus fumigatus infection is common in cystic fibrosis (CF) patients and estimates of the rate of allergic bronchopulmonary aspergillosis range from 1-15%. Voriconazole, a new triazole antifungal, has been recognised as efficient and safe in the treatment of invasive aspergillosis [1][2]. Since it is available orally, voriconazole became the first alternative to itraconazole. We began giving voriconazole to CF patients in 2003, and we encountered an unexpectedly high frequency of moderate-tosevere skin reactions, which limited the administration of the drug.We therefore reviewed all the medical files of children (aged ,18 yrs; n572) and adults (n563) followed up in our tertiary CF reference centre between April 2003 and December 2008, in order to estimate the frequency of voriconazole-induced photosensitivity, as previously defined [3]. All the patients who were given voraconazole were selected. Demographic data, cystic fibrosis transmembrane conductance regulator (CFTR) mutations, clinical data, treatment, duration and voriconazole dosage, and related adverse effects (AEs) were collected. Qualitative and quantitative comparisons were analysed using the Chi-squared test and nonparametric Mann-Whitney test, respectively. Multivariate analyses were performed by using stepwise logistic regression.A p-value ,0.05 was considered statistically significant. Statistical analyses were performed using Statistica 8 (StatSoft, MaisonsAlfort, France).

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Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults

Mangal

Hamadeh

Arwood

et al. 2018

Clin Pharma and Therapeutics

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Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady-state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5-7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model-based approach to predict doses that can maximize the net benefit (probability of efficacy-probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label-recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40-50% patients, with net benefit ranging from 5.8-61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300-600 mg were found to maximize the net benefit up to 51-66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.

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Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients

Abstract: In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.

Cited by 55 publications

References 34 publications

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

High frequency of voriconazole-related phototoxicity in cystic fibrosis patients

Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults

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