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Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections.

ABSTRACT: The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for ?7 days was completed. Patients receiving a fixed dose (i.e., labeled dose) were frequency matched and compared to those receiving a weight-based dose (i.e., high dose). The primary endpoint of hepatotoxicity was evaluated by using NCI Common Terminology Criteria (CTC) and components of liver enzymes measuring >3× the upper limit of normal (ULN) and >5× baseline measurements. Secondary endpoints included an incidence of other adverse drug events. Twenty-five labeled-dose and 84 high-dose voriconazole patients were studied. Liver enzyme abnormalities were similar between groups, with the exception of labeled-dose patients experiencing more alkaline phosphatase (ALP) CTC >2× the baseline (P = 0.02) and ALP levels >3× the ULN (P = 0.02). Treatment with high dose was associated with the discontinuation of voriconazole for practitioner attribution of adverse drug events (P = 0.03), although reasons varied and no commonality of biomarker abnormality was identified. Multivariate analysis revealed that the duration of therapy and higher mg/kg total daily doses as interval variables were predictive of some hepatotoxicity outcomes. No difference existed in liver abnormalities for high-dose voriconazole; however, higher mg/kg doses and a longer duration of therapy may be associated with hepatotoxicity.

SUBMITTER: Gorski E

PROVIDER: S-EPMC3019689 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections.

Gorski Elizabeth E Esterly John S JS Postelnick Michael M Trifilio Steven S Fotis Michael M Scheetz Marc H MH

Antimicrobial agents and chemotherapy 20101025 1

The approved treatment dose of intravenous voriconazole is a weight-based dose of 4 mg/kg of body weight twice daily; the approved oral dosing is fixed at 200 mg twice daily. In our institution, patients frequently receive oral high-dose voriconazole at 4 mg/kg twice daily. It is unknown if higher doses are associated with increased hepatotoxicity. A retrospective cohort study of patients treated with oral voriconazole for presumed invasive fungal infection for ≥7 days was completed. Patients re ...[more]

PMID: 20974867

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Project description:Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug-drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug-drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring.

Project description:Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Dataset Information

Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections.

Publications

Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections.

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