Dataset Information

Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels.

ABSTRACT: Voriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRC Cmin throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC Cmin (n = 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC Cmin inter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC Cmin (r = 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC Cmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRC Cmin/D than patients with a genetic score of >2 (P = 0.009). Subsequent VRC Cmin remained influenced by the genetic score (P = 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC Cmin in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC Cmin within the therapeutic range.

SUBMITTER: Gautier-Veyret E

PROVIDER: S-EPMC4356835 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels.

Gautier-Veyret Elodie E Fonrose Xavier X Tonini Julia J Thiebaut-Bertrand Anne A Bartoli Mireille M Quesada Jean-Louis JL Bulabois Claude-Eric CE Cahn Jean-Yves JY Stanke-Labesque Françoise F

Antimicrobial agents and chemotherapy 20150202 4

Voriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRC Cmin throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC Cmin (n = 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP45 ...[more]

PMID: 25645831

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Project description:Aims: To explore the interactive influence of glucocorticoids and cytochrome P450 (CYP450) polymorphisms on voriconazole (VRC) plasma trough concentrations (Cmin) and provide a reliable basis for reasonable application of VRC. Methods: A total of 918 VRC Cmin from 231 patients was collected and quantified using high-performance liquid chromatography in this study. The genotypes of CYP2C19, CYP3A4, and CYP3A5 were detected by DNA sequencing assay. The effects of different genotypes and the coadministration of glucocorticoids on VRC Cmin were investigated. Furthermore, the interactive effects of glucocorticoids with CYP450s on VRC Cmin were also analyzed. Results: The median Cmin of oral administration was lower than that of intravenous administration (1.51 vs. 4.0 mg l-1). Coadministration of glucocorticoids (including dexamethasone, prednisone, prednisolone, and methylprednisolone) reduced the VRC Cmin/dose, respectively, among which dexamethasone make the median of the VRC Cmin/dose ratio lower. As a result, when VRC was coadministrated with glucocorticoids, the proportion of VRC Cmin/dose in the subtherapeutic window was increased. Different CYP450 genotypes have different effects on the Cmin/dose of VRC. Mutations of CYP2C19*2 and *3 increased Cmin/dose of VRC, while CYP2C19*17 and CYP3A4 rs4646437 polymorphisms decreased Cmin/dose of VRC. The mutation of CYP3A5 has no significant effect. Furthermore, CYP2C19*17 mutants could strengthen the effects of glucocorticoids and decrease VRC Cmin/dose to a larger extent. Conclusion: Our study revealed that glucocorticoids reduced the Cmin/dose levels of VRC and different SNPs of CYP450 have different effects on the Cmin/dose ratio of VRC. Glucocorticoids and CYP2C19*17 mutants had a synergistic effect on reducing VRC Cmin/dose. The present results suggested that when VRC is combined with glucocorticoids, we should pay more attention to the clinical efficacy of VRC, especially when CYP2C19*17 mutants exist.

Project description:We sought to describe the clinical experience of voriconazole as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant recipients (allo-HCTr). This was a single-center retrospective study of adult allo-HCTr (1 January 2014 to 31 December 2016) who received ≥two doses of voriconazole-AFP. Voriconazole-AFP was started on day +7 post-HCT and continued at least through day +60 post-HCT, or longer as clinically indicated. We reviewed the rate, reasons, and risk factors of voriconazole-AFP discontinuation until day-100 post-HCT. A total of 327 patients were included. Voriconazole-AFP was continued for a median of 69 days (mean: 57.9; range 1, 100): for a median of 90 days (mean :84; range 2, 100) in 180/327 (55%) in the standard-of-care (SOC) group and 20 days (mean :25.6 ; range 1, 89; P-value < .001) in 147/327 (45%) patients in the early-discontinuation-group. Early-voriconazole-AFP discontinuation was due to adverse events, drug interactions, insurance coverage, and other reasons in 101/147 (68.7%), 27 (18.4%), 13 (8.8%), and 6 (4.1%) patients, respectively. Early-voriconazole-AFP discontinuation occurred in 73/327 (22.3%) patients due to hepatotoxicity. Important predictors for early-voriconazole-AFP discontinuation included: graft-versus-host disease grade ≥2 (odds ratio [OR]: 1.9, P-value: .02), alanine-aminotransferase ≥75 IU/ml on voriconazole-administration day-14 (OR: 5.6, P-value: .02) and total bilirubin ≥1.3 mg/dl on voriconazole-administration day-7 (OR: 3.0, P-value: .03). There were 13 proven/probable invasive fungal infections by day-180 post-HCT (8/147, 5.4%, and 5/180, 2.8% in the early-discontinuation and SOC-groups, respectively; log-rank:0.13). By day-180 post HCT, 23/147 (15.6%) and 14/180 (7.8%) patients in the early-discontinuation and SOC-groups had died, respectively (log-rank:0.03). Voriconazole-AFP was discontinued in up to 45% of allo-HCTr. Hepatotoxicity during the first 2 weeks post-HCT is a significant predictor of early-voriconazole-AFP discontinuation.

Project description:Voriconazole is frequently discontinued prematurely as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant (HCT) recipients due to adverse events. Limited data exists for isavuconazole as AFP. We analyzed adult HCT recipients who received voriconazole or isavuconazole AFP to estimate rate of premature AFP discontinuation, identify risk factors for premature AFP discontinuation, and compare incidence of invasive fungal infection (IFI) and survival at day + 180 post-HCT between patients who received voriconazole/isavuconazole-AFP. This was a propensity score matched cohort analysis of 210 HCT-recipients who received voriconazole-AFP (9/1/2014-12/31/2016; voriconazole-cohort), and 95 HCT-recipients who received isavuconazole-AFP (5/1/2017-10/31/2018; isavuconazole-cohort). AFP discontinuation for any reason prior to completion was defined as "premature". Median (interquartile range, IQR) duration of AFP was longer in the isavuconazole-cohort (94 days, 87-100) vs. the voriconazole-cohort (76 days, 23-94; P-value < 0.0001). Premature AFP discontinuation was more frequent in the voriconazole-cohort (92/210, 43.8%) vs. the isavuconazole-cohort (14/95, 14.7%; P-value < 0.0001). The most common reason for premature discontinuation was biochemical hepatotoxicity (voriconazole-cohort: 48/210, 22.8% vs. isavuconazole-cohort: 5/95, 5.26%; P-value = 0.0002). Transaminase values between baseline and end-of-treatment (EOT) and up to 14 days post-EOT significantly increased in the voriconazole-cohort, but remained unchanged in the isavuconazole-cohort. The incidence of IFI at day + 180 was 2.9% (6/210) and 3.2% (3/95) in the voriconazole-cohort and isavuconazole-cohort, respectively (P-value = 0.881). All-cause mortality at day + 180 was 2.4% (5/210) and 6.3% (6/95) in the voriconazole-cohort and isavuconazole-cohort, respectively (P-value = 0.089). When compared to voriconazole, isavuconazole was a safer and as effective primary AFP during the first 3 months after HCT.Lay summaryWhen compared to voriconazole, isavuconazole is a safer and as effective primary antifungal prophylaxis during the first 3 months after allogeneic hematopoietic cell transplant, with lower rates of hepatotoxicity, and similar rates of fungal infections and all-cause mortality.

Dataset Information

Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels.

Publications

Variability of voriconazole plasma concentrations after allogeneic hematopoietic stem cell transplantation: impact of cytochrome p450 polymorphisms and comedications on initial and subsequent trough levels.

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