Clinical Application of Voriconazole Concentrations in the Treatment of Invasive Aspergillosis

Howard, Ashley; Hoffman, Janet; Sheth, Anjly

doi:10.1345/aph.1l243

Cited by 50 publications

(48 citation statements)

References 16 publications

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“…It should be noted, however, that oral itraconazole capsules have low bioavailability, 22 and low-dose voriconazole may not reach the therapeutic serum levels. 23 Our data support the view that both regimens should not be considered as optimal prophylaxes in this setting. The low-dose voriconazole regimen was instituted to avoid interactions and hepatic toxicity, but the percentage of patients developing hypertransaminasemia was similar than in other studies using full dosage of voriconazole.…”

Section: Discussionsupporting

confidence: 82%

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Montesinos

Rodríguez‐Veiga

Boluda

et al. 2015

Bone Marrow Transplant

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Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT adult recipients surviving 440 days who engrafted and were discharged without prior IFD. All patients who received ⩾ 20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age 440 years, ⩾ 1 previous SCT, pre-engraftment neutropenia 415 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0-1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3-5 factors, CI 24.7%) (P o 0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment.

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Section: Discussionsupporting

confidence: 82%

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Montesinos

Rodríguez‐Veiga

Boluda

et al. 2015

Bone Marrow Transplant

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“…Although the poorer clinical response in patients with lower drug exposures is intuitively obvious and consistent with other studies (16,20,23), the lower rate of clinical response at higher concentrations is more difficult to understand. The extent of curvature, depicted in Fig.…”

Section: Discussionmentioning

confidence: 59%

Observational Study of the Clinical Efficacy of Voriconazole and Its Relationship to Plasma Concentrations in Patients

Troke¹,

Hockey²,

Hope

2011

Antimicrob Agents Chemother

193

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Voriconazole is approved for treating invasive fungal infections. We examined voriconazole exposureresponse relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (C avg ) and clinical response and between the free C avg /MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P < 0.001), therapy (primary/salvage, P < 0.001), primary diagnosis (P < 0.001), race (P ‫؍‬ 0.004), baseline bilirubin (P < 0.001), baseline alkaline phosphatase (P ‫؍‬ 0.014), and pathogen (yeast/mold, P < 0.001). The C avg for 72% of the patients was 0.5 to 5.0 g/ml, with the maximum response rate (74%) at 3.0 to 4.0 g/ml. The C avg showed a nonlinear relationship to response (P < 0.003), with a lower probability at the extremes. For patients with C avg < 0.5 g/ml, the response rate was 57%. The lowest response rate (56%) was seen with a C avg > 5.0 g/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P < 0.001) but not with voriconazole toxicity. Higher free C avg /MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes of C avg . Patients with higher free C avg /MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.

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“…Low troughs are associated with therapeutic failure among patients with IFIs, and dose adjustments for undetectable concentrations are reported to improve treatment efficacy (10,13,21,24,28,32,36,37,39). In some studies, elevated troughs are linked to increased toxicity, including central nervous system (CNS) events and elevated liver function tests (5,10,16,19,21,24,28,34). In general, a target trough range of 1 to 4 g/ml is recommended for treatment of IFIs (2, 7).…”

mentioning

confidence: 99%

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Mitsani

Nguyen

Shields

et al. 2012

Antimicrob Agents Chemother

118

125

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ABSTRACTVoriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n= 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n= 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P= 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P= 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (P= 0.01) and among patients with no trough of >1.5 μg/ml (P= 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P= 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.

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Clinical Application of Voriconazole Concentrations in the Treatment of Invasive Aspergillosis

Cited by 50 publications

References 16 publications

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Observational Study of the Clinical Efficacy of Voriconazole and Its Relationship to Plasma Concentrations in Patients

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

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