Voriconazole Cmin Research Articles

Impact of Inflammatory Burden on Voriconazole Exposure in Oncohematological Pediatric Patients Receiving Antifungal Prophylaxis after Allogeneic HCT.

(1) Background: The impact of inflammation on voriconazole exposure in oncohematological pediatric patients represents a debated issue. We aimed to investigate the impact of serum C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) levels on voriconazole exposure in oncohematological pediatric patients requiring allogeneic hematopoietic stem cell transplantation (HCT). (2) Methods: Pediatric patients undergoing allogeneic HCT and receiving therapeutic drug monitoring (TDM)-guided voriconazole as primary antifungal prophylaxis between January 2021 and December 2023 were included. The ratio between concentration and dose (C/D) of voriconazole was used as a surrogate marker of total clearance. A receiving operating characteristic curve analysis was performed by using CRP, PCT, or IL-6 values as the test variable and voriconazole C/D ratio > 0.188 or >0.375 (corresponding to a trough concentration value [Cmin] of 3 mg/L normalized to the maintenance dose of 16 mg/kg/day in patients of age < 12 years and of 8 mg/kg/day in those ≥12 years, respectively) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. (3) Results: Overall, 39 patients were included. The median (IQR) voriconazole Cmin was 1.7 (0.7-3.0) mg/L. A CRP value > 8.49 mg/dL (AUC = 0.72; 95%CI 0.68-0.76; p < 0.0001), a PCT value > 2.6 ng/mL (AUC = 0.71; 95%CI 0.63-0.77; p < 0.0001), and an IL-6 value > 27.9 pg/mL (AUC = 0.80; 95%CI 0.71-0.88; p < 0.0001) were significantly associated with voriconazole overexposure. Consistent results were found in patients aged <12 and ≥12 years. (4) Conclusions: A single specific threshold of inflammatory biomarkers may be linked to a significantly higher risk of voriconazole exposure in oncohematological pediatric patients after HCT, irrespective of age. Adopting a TDM-guided strategy could be useful for minimizing the risk of voriconazole overexposure.

Therapeutic Drug Monitoring of Voriconazole in Patients with End-Stage Liver Disease.

This study aimed to identify the factors that influence voriconazole (VCZ) plasma concentrations and optimize the doses of VCZ in patients with end-stage liver disease (ESLD). Patients with ESLD who received a VCZ maintenance dose of 100 mg twice daily (group A, n = 57) or the VCZ maintenance dose of 50 mg twice daily (group B, n = 37), orally or intravenously, were enrolled in this study. Trough plasma concentrations (Cmin) of VCZ between 1 and 5 mg/L were considered within the therapeutic target range. The VCZ Cmin was determined in 94 patients with ESLD. The VCZ Cmin of patients in group A was remarkably higher than those in group B (4.85 ± 2.53 mg/L vs 2.75 ± 1.40 mg/L; P < 0.001). Compared with group A, fewer patients in group B had VCZ Cmin outside the therapeutic target (23/57 vs. 6/37, P = 0.021). Univariate and multivariate analyses suggested that both body weight and Model for End-Stage Liver Disease scores were closely associated with the VCZ Cmin in group B. These data indicate that dose optimization based on body weight and Model for End-Stage Liver Disease scores is required to strike an efficacy-safety balance during VCZ treatment in patients with ESLD.

Combined impact of hypoalbuminemia and pharmacogenomic variants on voriconazole trough concentration: data from a real-life clinical setting in the Chinese population

Voriconazole (VRC) displays highly variable pharmacokinetics impacting treatment efficacy and safety. To provide evidence for optimizing VRC therapy regimens, the authors set out to determine the factors impacting VRC steady-state trough concentration (Cmin) in patients with various albumin (Alb) level. A total of 275 blood samples of 120 patients and their clinical characteristics and genotypes of CYP2C19, CYP3A4, CYP3A5, CYP2C9, FMO3, ABCB1, POR, NR1I2 and NR1I3 were included in this study. Results of multivariate linear regression analysis demonstrated that C-reactive protein (CRP) and total bilirubin (T-Bil) were predictors of the VRC Cmin adjusted for dose in patients with hypoalbuminemia (Alb < 35 g/L) (R 2 = 0.16, P < 0.001). Additionally, in patients with normal albumin level (Alb ≥ 35 g/L), it resulted in a significant model containing factors of the poor metabolizer (PM) CYP2C19 genotype and CRP level (R2 = 0.26, P < 0.001). Therefore, CRP and T-Bil levels ought to receive greater consideration than genetic factors in patients with hypoalbuminemia.

Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study.

Voriconazole, an antifungal agent, displays high intra- and inter-individual variability. The predictive pharmacokinetic (PK) index requires a minimum plasma concentration (Cmin) in patient serum of between 1-5.5 mg/L. It is common to encounter fungal infections in patients undergoing extracorporeal membrane oxygenation (ECMO) support, and data regarding voriconazole PK changes during ECMO are scarce. Our study compared voriconazole PKs in patients with and without ECMO support in a retrospective cohort of critically-ill patients. Fifteen patients with 26 voriconazole Cmin determinations in the non-ECMO group and nine patients with 27 voriconazole Cmin determinations in the ECMO group were recruited. The ECMO group had lower Cmin (0.38 ± 2.98 vs. 3.62 ± 3.88, p < 0.001) and higher infratherapeutic Cmin values (16 vs. 1, p < 0.001) than the non-ECMO group. Multivariate analysis identified ECMO support (-0.668, CI95 -0.978--0.358) and plasma albumin levels (-0.023, CI95 -0.046--0.001) as risk factors for low Cmin values. When comparing pre- and post-therapeutic drug optimisation samples from the ECMO group, the dose required to achieve therapeutic Cmin was 6.44 mg/kg twice a day. Therapeutic drug optimisation is essential to improve target attainment.

Impact of Inflammation on Voriconazole Exposure in Critically ill Patients Affected by Probable COVID-19-Associated Pulmonary Aspergillosis.

(1) Background: To explore the impact of the degree of inflammation on voriconazole exposure in critically ill patients affected by COVID-associated pulmonary aspergillosis (CAPA); (2) Methods: Critically ill patients receiving TDM-guided voriconazole for the management of proven or probable CAPA between January 2021 and December 2022 were included. The concentration/dose ratio (C/D) was used as a surrogate marker of voriconazole total clearance. A receiving operating characteristic (ROC) curve analysis was performed by using C-reactive protein (CRP) or procalcitonin (PCT) values as the test variable and voriconazole C/D ratio > 0.375 (equivalent to a trough concentration [Cmin] value of 3 mg/L normalized to the maintenance dose of 8 mg/kg/day) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated; (3) Results: Overall, 50 patients were included. The median average voriconazole Cmin was 2.47 (1.75-3.33) mg/L. The median (IQR) voriconazole concentration/dose ratio (C/D) was 0.29 (0.14-0.46). A CRP value > 11.46 mg/dL was associated with the achievement of voriconazole Cmin > 3 mg/L, with an AUC of 0.667 (95% CI 0.593-0.735; p < 0.001). A PCT value > 0.3 ng/mL was associated with the attainment of voriconazole Cmin > 3 mg/L (AUC 0.651; 95% CI 0.572-0.725; p = 0.0015). (4) Conclusions: Our findings suggest that in critically ill patients with CAPA, CRP and PCT values above the identified thresholds may cause the downregulation of voriconazole metabolism and favor voriconazole overexposure, leading to potentially toxic concentrations.

Factors Influencing and Adverse Reactions of Voriconazole Clearance in Patients with Hematological Diseases

To monitor the changes of voriconazole minimum concentration(Cmin) in patients with hematological diseases, and evaluate the factors influencing and adverse reactions of voriconazole clearance in patients with hematological diseases, so as to provide a theoretical basis for reasonable clinical use of voriconazole. 136 patients with hematological diseases who used voriconazole in Wuhan NO.1 Hospital from May 2018 to December 2019 were selected. The correlation between C-reactive protein, albumin, creatinine and voriconazole Cmin were analyzed, and the changes of voriconazole Cmin after glucocorticoid treatment was also detected. In addition, stratified analysis was used to explore the adverse events of voriconazole. Among 136 patients, 77 were male (56.62%) and 59 were female (43.38%). There were positive correlations between voriconazole Cmin and C-reactive protein and creatinine levels (r=0.277, r=0.208), while voriconazole Cmin was negatively correlated with albumin level (r=-2.673). Voriconazole Cmin in patients treated with glucocorticoid was decreased significantly (P<0.05). In addition, sratified analysis of voriconazole Cmin showed that compared with voriconazole Cmin 1.0-5.0 mg/L group, the incidence of adverse reactions of visual impairment in voriconazole Cmin> 5.0 mg/L group was increased (χ2=4.318, P=0.038). The levels of C-reactive protein, albumin and creatinine are closely related to the voriconazole Cmin, which indicate that inflammation and hyponutrition may prevent the clearance of voriconazole in patients with hematological diseases. It is necessary to monitor the voriconazole Cmin of patients with hematological diseases, and adjust the dosage in time to reduce adverse reactions.

Factors Influencing Blood Concentration of Voriconazole and Therapeutic Drug Monitoring in Patients with Child–Pugh Class C Cirrhosis

What Is Known and Objective. CYP2C19 is an important influencing factor for voriconazole trough plasma concentration (Cmin); however, it is not verified in Child–Pugh C (CP-C) cirrhosis patients, and no voriconazole dosage regimen is recommended for these patients in the package insert. This retrospective study identified CYP2C19 and other factors influencing voriconazole Cmin for CP-C cirrhosis, and obtained an appropriate method of application of voriconazole for them. Methods. A total of 66 patients with CP-C cirrhosis who accepted voriconazole therapy were involved. The voriconazole Cmin, clinical characteristics, CYP2C19 genotype, and adverse effects (AEs) were recorded and analyzed. Results. Unlike other research studies, voriconazole Cmin was not different among normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) of the CYP2C19 enzyme in CP-C cirrhosis ( P &gt; 0.05). The maintenance dose regimen for voriconazole was the only independent influencing factor for Cmin ( P = 0.045; OR = 3.753; 95% CI, 1.029–13.694). At about 1/3 of the recommended maintenance dose, only 16.7% (8/48) had Cmin &gt;5.5 μg/mL, 4.5% (3/48) had Cmin &lt;1 μg/mL, and only one AE happened. There were four voriconazole-related AEs that happened in this study, and three AEs occurred (3/4, 75%) when the maintenance dose was not adjusted with therapeutic drug monitoring (TDM). What Is New and Conclusion. Voriconazole Cmin did not significantly vary according to CYP2C19 enzyme metabolization status (being an NM, IM, or PM) in CP-C cirrhosis. Reducing the maintenance dose of voriconazole to approximately 1/3 the standard maintenance dose and administering in combination with TDM in patients with CP-C cirrhosis are recommended.

Contribution of voriconazole N-oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection.

Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. Based on 225 measurements, the median and interquartile range were 2.4μg/ml (1.2; 4.2), 2.1μg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2μg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2μg/ml and above 5.5μg/ml, respectively, at the next visit. Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.

Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study

To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.

Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: A retrospective study.

Aims: We aimed to assess the impact of extracorporeal membrane oxygenation (ECMO) on voriconazole exposure. Methods: Adult critically ill patients with or without ECMO support receiving intravenous voriconazole therapy were included in this retrospective study conducted in a tertiary referral intensive care unit. The first therapeutic drug monitoring (TDM) results of voriconazole in ECMO patients and non-ECMO patients were collected, and the prevalence of subtherapeutic concentrations was analyzed. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure. Results: A total of 132 patients (including 66 patients with ECMO support) were enrolled and their respective first voriconazole trough concentrations (Cmin) were recorded. The median Cmin of the ECMO group and the non-ECMO group was 1.9 (1.4–4.4) and 4.4 (3.2–6.9) mg/L, respectively (p = 0.000), and the proportion of the two groups in subtherapeutic concentrations range (<2 mg/L) was 51.5% and 7.6%, respectively (p = 0.000). Multiple linear regression analysis of voriconazole Cmin identified that the use of ECMO and coadministration of glucocorticoids were associated with significantly reduced concentrations, while increasing SOFA score and increasing daily dose were associated with significantly increased concentrations. The model accounted for 32.2% of the variability of voriconazole Cmin. Furthermore, binary logistic regression demonstrated that the use of ECMO was an independent risk factor (OR = 7.78, p = 0.012) for insufficient voriconazole exposure. Conclusion: Our findings showed that, in addition to the known drug interactions, ECMO is a significant covariable affecting voriconazole exposure. In addition, SOFA score was identified as a factor associated with increased voriconazole concentration.

Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole.

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.

The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2 =44%, p<.00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2 =46%, p<.00001) had significantly higher voriconazole Cmin (μg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2 =0%, p=.0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2 =22%, p=.003). Similarly, the Cmin /D (μg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2 =0%, p=.002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2 =0%, p=.003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2 =0%, p<.00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2 =50%, p=.005). Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.

Using Child-Pugh Class to Optimize Voriconazole Dosage Regimens and Improve Safety in Patients with Liver Cirrhosis: Insights from a Population Pharmacokinetic Model-based Analysis.

Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients. Retrospective pharmacokinetics study. Two large, academic, tertiary-care medical center. Two hundred nineteen plasma trough concentrations (Cmin ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non-cirrhotic patients were included. Data pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model-based simulation was used to optimize voriconazole dosage regimens. Voriconazole-related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold Cmin for AE was 5.12mg/L. A two-compartment model with first-order elimination adequately described the data. The Child-Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non-cirrhotic, Child-Pugh class A and B cirrhotic (CP-A/B) and Child-Pugh class C cirrhotic (CP-C) patients was 7.59, 1.86, and 0.93L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model-based simulations showed that a loading dose regimen of 200mg/12hours intravenously or orally led to 65.0-75.7% of voriconazole Cmin in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75mg/12hours and 150mg/24hours intravenously or orally for CP-A/B patients, and 50mg/12hours and 100mg/24hours intravenously or orally for CP-C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady-state was 66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients. These results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/B patients compared to that for patients with normal liver function.

Optimization of voriconazole therapy for treatment of invasive aspergillosis: Pharmacogenomics and inflammatory status need to be evaluated.

Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (<1mg/L). The genetic score was determined in hematological patients treated with VRC. The higher the genetic score, the faster the metabolism of the patient. The impact of the genetic score was evaluated considering initial VRC Cmin and all VRC Cmin (n=159) determined during longitudinal therapeutic drug monitoring. Forty-three patients were included, of whom 41 received VRC for curative indication. Thirty-six patients had a genetic score ≥2, of whom 11 had an initial insufficient VRC Cmin . A genetic score ≥2 had a positive predictive value of 0.31 for having an initial insufficient VRC Cmin and initial VRC Cmin was not associated with the genetic score. The lack of association between the genetic score and VRC Cmin may be related to the inflammatory status of the patients (C-reactive protein [CRP] levels: median [Q1-Q3]: 43.0 [11.0-110.0]mg/L), as multivariate analysis performed on all VRC Cmin identified CRP as an independent determinant of the VRC Cmin adjusted for dose (P<.0001). The combined genetic score did not predict low VRC exposure in patients with inflammation, which is frequent in patients with invasive fungal infections. Strategies for the individualization of VRC dose should integrate the inflammatory status of patients in addition to pharmacogenetic variants.

Impact of dose adaptations following voriconazole therapeutic drug monitoring in pediatric patients.

Voriconazole is the mainstay of treatment for invasive aspergillosis in immunocompromised pediatric patients. Although Therapeutic Drug Monitoring (TDM) of voriconazole is recommended, it remains unknown if TDM-based dose adaptations result in target attainment. Patients <19 years from two pediatric hematologic-oncology wards were retrospectively identified based on unexplained high voriconazole trough concentrations (Cmin >6mg/l). Patient demographics, clinical characteristics, treatment, voriconazole dosing information, voriconazole Cmin before and after adjustment based on TDM were obtained. Twenty-one patients, median (range) age 7.0 (1.2-18.5) years, were identified in two centers. First Cmin (3.1mg/l [0.1-13.5]) was obtained after 3 days (1-27) of treatment. The median of all Cmin (n = 485, median 11 per patient) was 2.16mg/l (0.0 (undetectable)-28.0), with 24.1% of Cmin < 1mg/l, 48.9% 1-4mg/l, 9.3% 4-6mg/l, and 17.7% >6mg/l. Intrapatient variability was large (94.1% for IV, 88.5% for PO). Dose increases at Cmin < 1mg/l resulted in an increased Cmin in 76.4%, with 60% between 1 and 4mg/l. Dose decreases at Cmin >6mg/l resulted in a decreased Cmin in 80%, with 51% between 1 and 4mg/l. Overall, in 45% of the cases (33 out of 55 and 12 out of 45) therapeutic targets were attained after dose adjustment. Fifty-five percent of initial Cmin was outside the therapeutic target of 1-4mg/l, with multiple dose adaptations required to achieve therapeutic concentrations. Only 60% and 51% of dose adaptations following sub- and supra-therapeutic Cmin, respectively, did result in target attainment. Intensive and continuous TDM of voriconazole is a prerequisite for ensuring adequate exposure in pediatric patients.

Inflammation is a potential risk factor of voriconazole overdose in hematological patients.

Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin ) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi-square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.

A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.

Voriconazole is a broad-spectrum antifungal agent and is mainly metabolized by the liver, yet there have been no reports about voriconazole treatment in patients with Child-Pugh class C cirrhosis. The objective of this study was to investigate the pharmacokinetic profile and safety of voriconazole treatment in this cohort of patients. A retrospective, multicenter study was performed in patients with Child-Pugh class C cirrhosis who received a voriconazole maintenance dose of 100mg twice daily (group A) or 200mg daily (group B) orally or intravenously. All voriconazole Cmin were measured by high-performance liquid chromatography, and voriconazole-related adverse events were defined according to Common Terminology Criteria for Adverse Events. The relationship between voriconazole Cmin and adverse events was explored using logistic regression model. A total of 51 voriconazole Cmin were monitored from 34 patients. The Cmin of voriconazole was 4.42±2.08 and 5.42±1.96mg/L in groups A and B, respectively. The proportion of voriconazole Cmin over the upper limit of therapeutic level (5mg/L) in groups A and B was 34.48% and 47.62%, respectively. Additionally, 23.5% (8/34) of patients exhibited signs of voriconazole-related adverse events, and 87.5% (7/8) of adverse events occurred within the first week after voriconazole treatment. Logistic regression model showed that there was a positive correlation between voriconazole Cmin and the incidence of adverse reactions. Voriconazole Cmin value of 4.5mg/L was associated with a 20% probability of adverse events. The voriconazole maintenance dose of 100mg twice daily or 200mg daily orally or intravenously may be inappropriate in patients with Child-Pugh class C cirrhosis because of the higher voriconazole Cmin and higher incidence of adverse events. Monitoring voriconazole Cmin earlier is extremely important to prevent the occurrence of voriconazole-related adverse reactions.

Therapeutic drug monitoring and safety of voriconazole therapy in patients with Child–Pugh class B and C cirrhosis: A multicenter study

ObjectivesThe purpose of this study was to investigate the pharmacokinetic profile and safety of voriconazole treatment in patients with Child–Pugh class B and C cirrhosis. MethodsLiver cirrhosis patients who had received the recommended voriconazole maintenance dose (group A) or halved maintenance dose (group B), orally or intravenously, were included. Voriconazole-related adverse events (AEs) were defined according to the Common Terminology Criteria for Adverse Events. ResultsA total of 110 trough plasma concentrations of voriconazole (Cmin) were measured in 78 patients. There was a significant difference in voriconazole Cmin between group A and group B (Cmin, 6.95±3.42mg/l vs. 4.02±2.00mg/l; p<0.001). No significant difference in voriconazole Cmin between Child–Pugh class B and C cirrhosis patients was observed in either of the two groups. The international normalized ratio and co-medication with a CYP2C19 inhibitor had a significant effect on voriconazole Cmin in group B. The incidence of AEs in group A was 26.5% and in group B was 15.9%, and 87.5% of AEs developed within 7days after starting voriconazole treatment. ConclusionsThese results suggest that the recommended dose and halved maintenance dose may be inappropriate in patients with Child–Pugh class B and C cirrhosis due to the high Cmin, and that voriconazole Cmin should be monitored earlier to avoid AEs.

Voriconazole therapeutic drug monitoring: Factors associated with supratherapeutic and subtherapeutic voriconazole concentrations.

The voriconazole trough concentration (C_min) varies widely, and C_min outside the therapeutic range (COTR) is associated with response failure and toxicity. The objective of this study was to identify potential factors associated with COTR in patients, and specifically the population at a high risk of COTR. We performed a retrospective study of patients who received voriconazole from 2009 to 2016. Voriconazole C_min values were analyzed with high-performance liquid chromatography, and values of <1mg/L and >4mg/L were defined as COTR. Logistic regression and the classification and regression tree (CART) were used to explore the potential factors associated with COTR. In total, 134 voriconazole C_min values were measured in 64 patients who met the eligibility criteria: 55 (41.0%) were subtherapeutic, and 79 (59.0%) were supertherapeutic. Logistic regression revealed that voriconazole COTR was significantly associated with age, CYP2C19 genetic status, and liver function after voriconazole treatment. CART identified the high-risk population of COTR: (1) patients' age <47 years and with underlying liver disease, (2) patients' age >47 years and with acute liver dysfunction after voriconazole treatment, (3) non-poor metabolizers, aged from 46 to 65 years and with normal liver function after voriconazole treatment, and (4) old (age >65 years) patients with normal liver function and body weight <66kg. Our findings suggest that age, CYP2C19 genetic status, and liver function status are strongest predictors of voriconazole COTR. Clinically, these results can be used to estimate the probability of voriconazole COTR in individual patients. .

Pharmacogenetics may Influence the Impact of Inflammation on Voriconazole Trough Concentrations

How pharmacogenetics modulates the inhibitory effects of inflammation on voriconazole trough concentration (Cmin) remains unknown. In 29 recipients of allogeneic hematopoietic stem cell transplantation retrospectively studied, both a genetic score (which aggregated CYP2C19 and CYP3A genotypes) and inflammation significantly influenced voriconazole Cmin (n = 260). A trend toward (p = 0.03) a greater impact of inflammation in patients with the highest genetic score (corresponding to ultra-rapid metabolizers) was observed. Further researches are needed to confirm these data.