Hepatic Safety of Voriconazole after Allogeneic Hematopoietic Stem Cell Transplantation

Department of Medicine, Service of Infectious Disease, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.4). 01/2010; 16(1):46-52. DOI: 10.1016/j.bbmt.2009.08.015
Source: PubMed


Voriconazole is increasingly used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis and treatment of fungal infections. Hepatic dysfunction is common in patients undergoing HSCT and may have an impact on the clinical decision to institute voriconazole. We conducted a retrospective review of all adult and pediatric HSCT recipients who received >2 consecutive doses of voriconazole between January 2005 and February 2008. Clinical hepatotoxicity was defined as the subjective attribution of liver enzyme elevation (even a mild one) to hepatotoxicity because of voriconazole by the treating physician and leading to discontinuation of voriconazole. Biochemical hepatotoxicity was defined as an elevation in one or more liver enzymes to >3 times the upper limit of normal or >3 times the baseline value if abnormal at baseline. Liver enzymes assessed included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin. Simple and multiple logistic regressions were used to define the risks for hepatic dysfunction. The Wilcoxon signed-rank test was used to assess the differences in liver function test values before, during, and after the use of voriconazole. Sixty-eight of 200 patients (34%) developed hepatotoxicity while on voriconazole. The median duration of voriconazole therapy was 72 days (range, 1-804 days). Biochemical hepatotoxicity occurred in 51 patients (75%); clinical hepatotoxicity, in 17 patients (25%). Thirty-five (51%) of the patients with hepatotoxicity required discontinuation of therapy. In simple logistic regression, acute graft-versus-host disease (GVHD) was a risk factor for hepatotoxicity, and receipt of a T-cell depleted allograft was protective. In multiple logistic regression, acute GVHD (P = .002) remained significant. There were no cases of liver failure or death attributed to voriconazole. In this cohort of patients undergoing allogeneic HSCT, the rate of hepatotoxicity while on voriconazole was 34%. In general, the hepatic dysfunction was mild and reversible. Voriconazole therapy with monitoring appears to be reasonably safe for use in HSCT recipients at high risk for invasive fungal infections.

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    • "A recently published review reported that 19.7% of 881 patients treated with voriconazole had elevated serum liver enzymes, but they did not require drug withdrawal (Wang et al., 2010). A retrospective study conducted on HSCT patients by Amigues et al. (2010) reports a hepatotoxicity frequency of 34% while on voriconazole and therapy discontinuation rate of 51%, with graft-versus-host disease being the only significant factor linked to hepatotoxicity. "
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    ABSTRACT: We aimed to investigate the role of several host factors as predictors of mortality in non-neutropenic patients with invasive pulmonary aspergillosis (IPA). Contribution of respiratory galactomannan (GM) index was evaluated as well. In this retrospective study we examined 27 patients with “proven” and “probable” IPA. Outcome measured was death within 6-week from diagnosis of possible IPA. Overall mortality was 33.3%. At univariate analysis, Nonsurvivors were statistically more likely to be affected with cirrhosis. No independent variables predicting mortality were identified in the multivariate model. Mean BAL GM index value in the nonsurvivor group was significantly higher. A GM index cutoff value ≥ 2.0 is able to classify patients with a poor outcome with a sensitivity of 100% and a specificity of 77%. Liver cirrhosis is a predictor of mortality in patients with IPA. GM index in BAL might be considered as a valuable tool in classifying patients at risk of poor outcome.
    Diagnostic Microbiology and Infectious Disease 05/2014; DOI:10.1016/j.diagmicrobio.2014.05.015 · 2.46 Impact Factor
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    • "An average CsA dose reduction of 22% (range, 10 - 32%) was sufficient to adjust for this reaction. Similar elevated CsA trough levels were also observed in up to 41% of patients in another retrospective review of adult and pediatric HSCT recipients after voriconazole administration [27]. The limitations of the measured posaconazole levels in our analysis are that they took place retrospectively from excess material remaining after laboratory analyses which had been routinely cryopreserved, and that only on arbitrary time points after day seven (the point commonly known to be the time when a steady state of posaconazole levels plasma is reached) were possible. "
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    ABSTRACT: Background Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Antifungal prophylaxis shortly after transplantation is therefore indicated, but data for pediatric patients under 12 years of age are scarce. To address this issue, we retrospectively assessed the safety, feasibility, and initial efficacy of prophylactic posaconazole in children. Methods 60 consecutive pediatric patients with a median age of 6.0 years who underwent allogeneic HSCT between August 2007 and July 2010 received antifungal prophylaxis with posaconazole in the outpatient setting. 28 pediatric patients received an oral suspension at 5 mg/kg body weight b.i.d., and 32 pediatric patients received the suspension at 4 mg/kg body weight t.i.d. The observation period lasted from start of treatment with posaconazole until its termination (maximum of 200 days post-transplant). Results Pediatric patients who received posaconazole at 4 mg/kg body weight t.i.d. had a median trough level of 383 μg/L. Patients who received posaconazole at 5 mg/kg body weight b.i.d. had a median trough level of 134 μg/L. Both regimens were well tolerated without severe side effects. In addition, no proven or probable invasive mycosis was observed. Conclusion Posaconazole was a well-tolerated, safe, and effective oral antifungal prophylaxis in pediatric patients who underwent high-dose chemotherapy and HSCT. Posaconazole at a dosage of 12 mg/kg body weight divided in three doses produced consistently higher morning trough levels than in patients who received posaconazole 5 mg/kg body weight b.i.d. Larger prospective trials are needed to obtain reliable guidelines for antifungal prophylaxis in children after HSCT.
    BMC Infectious Diseases 10/2012; 12(1):263. DOI:10.1186/1471-2334-12-263 · 2.61 Impact Factor
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    ABSTRACT: To identify patient-specific factors significantly associated with voriconazole exposure. DESIGN SETTING, AND PARTICIPANTS: Retrospective, single center at an academic medical center. Consecutive, adult oncology inpatients who received voriconazole by mouth and had at least one voriconazole level over a 14-month period. Voriconazole was ordered for 292 patients during the study period, a level was obtained in 41 patients. Nine patients were excluded; the study population was comprised of 32 patients. Univariate and multivariable regression analyses were utilized to predict the patient-specific factors significantly associated with level. A total of 36 levels meeting inclusion/exclusion criteria were performed in 32 patients. Sixty percent of levels (22/36) were between 1 and 5.5 µg/mL. Data were available to calculate a Child Pugh score for 66% (21/32) of patients. Using multivariable linear regression, three covariates were found to be statistically significant: age, international normalized ratio (INR), and alkaline phosphatase (ALP). Three outliers were notable in the ALP category, when removing the three individuals from the model, only an increasing INR remains significantly associated with increasing voriconazole level (p = 0.0093). No correlation was found with trough level and Child Pugh score. Sixty percent of voriconazole trough levels were between 1 and 5.5 µg/mL (range 0.1-7.4 µg/mL), only increasing INR was significantly associated with rising voriconazole level. Increasing Child Pugh score was not associated with increasing level. More investigation is warranted into the usefulness of the Child Pugh score for guidance of dose modifications in non-cirrhotic patients with acute hepatic injury.
    Journal of Oncology Pharmacy Practice 02/2011; 18(1):3-9. DOI:10.1177/1078155210397963
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