Influencing risk factors of voriconazole-induced liver injury in Uygur pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

PURPOSE: We aimed to investigated the influencing risk factors of voriconazole-induced liver injury in Uygur pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: This was a prospective cohort design study. High-performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentration. First-generation sequencing was performed to detect gene polymorphisms. Indicators of liver function were detected at least once before and after voriconazole therapy. RESULTS: Forty-one patients were included in this study, among which, 15 patients (36.6%) had voriconazole-induced liver injury. The proportion of voriconazole trough concentration > 5.5 µg·mL-1 patients within the DILI group (40.0%) was significantly higher compared to the control group (15.4%) (p < 0.05). After administration of voriconazole, the values of ALT (103.3 ± 80.3 U/L) and AST (79.9 ± 60.6 U/L) in the DILI group were higher than that in the control group (24.3 ± 24.8 and 30.4 ± 8.6 U/L) (p < 0.05). There was no significant difference between the two groups in genotype and allele frequencies of CYP2C19*2, CYP2C19*3, CYP2C19*17, and UGT1A4 (rs2011425) (p > 0.05). CONCLUSION: There was a significant correlation between voriconazole-induced liver injury and voriconazole trough concentration in high-risk Uygur pediatric patients with allogeneic HSCT.

Clinically relevant bidirectional drug-drug interaction between midostaurin and voriconazole.

Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L-1 , target Ctrough 1-5 mg L-1 ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

BACKGROUND: Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. METHODS: This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. RESULTS: A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. CONCLUSION: Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.

Accelerated photocarcinogenesis and multifocal squamous cell carcinomas associated with voriconazole and human papillomavirus in HIV - case report.

Voriconazole is an antifungal with known side effects of phototoxicity and photocarcinogenesis. We present a case of HPV-related multifocal squamous cell carcinoma in a 68-year-old man with HIV, due to accelerated photocarcinogenesis associated with long-term use of voriconazole. Histology confirmed SCC with HPV-related features and he was found to have metastases. Multifocal SCC is unusual in association with voriconazole and HIV infection and only one other case has been reported. It is important for clinicians to be aware of the photocarcinogenic effects of voriconazole, especially in patients with HIV.

Evaluation of voriconazole related adverse events in pediatric patients with hematological malignancies.

BACKGROUND: Despite therapeutic drug monitoring and pharmacogenetic-guided dose selection are recommended for pediatric patients, safety of voriconazole is mostly monitored by clinical assessment. Having comprehensive knowledge of safety profile and distinguishing incidental events from the reactions that are truly related to voriconazole use are crucial for safer and uninterrupted treatment. OBJECTIVES: This study aimed to address adverse reactions during the first month of voriconazole use by systematically evaluating retrospective records of all adverse events. Patients/Methods: It is a single-center, retrospective analysis of patients who received voriconazole from 1 September 2010 to 1 September 2020. Severity of abnormal findings in medical records were systematically graded. Causality between voriconazole and the events was evaluated by Liverpool Causality Assessment Tool (LCAT), Naranjo Algorithm and World Health Organization Causality Assessment System. The events with possible or probable causal relation to voriconazole are classified as adverse reaction. RESULTS: Records of 45 patients included in the study. The overall frequency of adverse reactions was 51.1%. Hepatobiliary laboratory adverse reactions identified in 48.9% of the patients and led to treatment discontinuation in 20.0%. Amylase and lipase elevation (2.2%), ventricular extra systoles (2.2%), hallucination and nightmares (2.2%) were other adverse reactions. CONCLUSIONS: Hepatobiliary abnormalities were the most common adverse reactions and the most common cause of treatment discontinuation. For safer treatment in critically ill patients, the dose should be personalized. To clearly identify the accurate frequency and the causality of all adverse reactions, prospective studies with much larger sample size are needed.

Safety of an Intravenous Formulation of Voriconazole as an Intramuscular Injection in Pigeons (Columba livia f. domestica).

Aspergillosis is a common disease in birds. Currently, avian aspergillosis is treated with voriconazole administered orally, although intramuscular (IM) administration increases bioavailability and is more effective in treating generalized aspergillosis. The objective of this study was to evaluate the safety of the intravenous formulation of voriconazole as an IM injection in the pectoral muscles of pigeons (Columba livia f. domestica) as a model for other avian species. Sixteen healthy pigeons received IM injections of voriconazole (12.5 mg/kg) and sterile saline in the right and left pectoral muscles, respectively, twice a day for 7 days. Additionally, 4 birds acted as controls (no injections). Eight birds in the treatment group and 2 of the control pigeons were humanely euthanized 1 day (group 1) and 14 days (group 2) after the final injection. Hematologic and plasma biochemistry panels were performed prior to the birds being euthanized. Gross and histopathological evaluations of the pectoral muscles were completed postmortem. Statistical analysis revealed significant differences in multiple parameters, including aspartate aminotransferase and lactate dehydrogenase, but all biochemical analytes remained within the reference intervals for the species. The group 1 birds had advanced gross and histopathological pectoral muscle lesions associated with the voriconazole injections compared with the contralateral side, the group 2 birds, and the negative controls. After 14 days, the pectoral muscles did not reveal any gross or histopathological changes associated with the voriconazole or sterile saline injections. These results indicate that the intravenous formulation is safe for IM use twice per day for 1 week in pigeons. Further investigation is needed to extrapolate these findings to other avian species and to evaluate the roles of longer treatment periods and higher doses of voriconazole.

Occurrence of voriconazole-induced cutaneous squamous cell carcinoma in Japan: data mining from different national pharmacovigilance databases.

Long-term voriconazole use may increase the risk of cutaneous squamous cell carcinoma (cSCC), especially in immunocompromised patients. However, relatively little is known regarding voriconazole-induced cSCC in Japan. Thus, the purpose of this study was to evaluate the association between voriconazole use and cSCC in Japan using different national pharmacovigilance databases. First, using the Japanese Adverse Drug Event Report (JADER) database, we evaluated the association between voriconazole use and cSCC in Japan. Second, using the U. S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, we examined regional differences in the occurrence of voriconazole-induced cSCC between Japan and other countries. We calculated reporting odds ratios (RORs) as disproportionality analysis to evaluate voriconazole-induced cSCC. In this study, cases in which one or more of "Bowen's disease", "Carcinoma in situ of skin", "Keratoacanthoma", "Squamous cell carcinoma in skin", or "Squamous cell carcinoma" were reported as adverse events were considered to be cSCC cases. The analysis based on the JADER database showed an association between voriconazole use and cSCC in Japan, with a ROR (95% confidence interval) of 35.37 (25.60-48.87). Further, the analysis based on the FAERS database revealed that signals were detected in Japan as well as in Western countries and Australia. This study is the first in which the association between voriconazole use and cSCC in Japan is assessed using national pharmacovigilance databases. Healthcare providers need to be fully aware of the potential for cSCC development owing to voriconazole use and in all countries, including Japan, ensure careful follow-up of patients' skin.

Efficacy and safety of voriconazole as invasive fungal infection prophylaxis in patients with acute myeloid leukemia.

Invasive fungal infections (IFIs) are commonly observed in patients, who are at high risk of severe infections during the neutropenic phase. The aim of this retrospective single-center study was to evaluate the efficacy and safety of voriconazole as a fungal prophylaxis after induction chemotherapy for acute myeloid leukemia (AML) in adult patients. Six proven/probable IFIs were diagnosed in 213 patients with AML (median age 61 years, range 18-85), who received a total of 377 induction chemotherapies. This yielded an incidence rate of 1.6% based on all induction cycles administered. Voriconazole prophylaxis was administered as intended in 317 out of 377 (84%) induction cycles until the end of neutropenia with a median duration of 20 days (range: 2-101 days). In conclusion, voriconazole demonstrates efficacy and safety as a first-line IFI prophylaxis comparable to published data on posaconazole, which is the standard fungal prophylaxis recommendation for AML patients in international guidelines today.

Spectrum of voriconazole-associated periostitis in clinical characteristics, diagnosis and management.

PURPOSE: Previous knowledge about the relationship between voriconazole exposure and periostitis was mainly based on limited case reports and few retrospective studies. The purpose of this study was to assess the clinical characteristics, diagnosis and management of voriconazole-associated periostitis. METHODS: Case reports and case series from 1998 to November 30, 2021 on periostitis induced by voriconazole were collected for retrospective analysis. RESULTS: Forty four patients (18 male and 26 female) from 34 studies were included in total. The median age was 58 years (29-74). The majority of patients had undergone organ transplantation (50.0%) or suffered from hematologic malignancy (31.81%). The median onset time of symptoms was 6 months after the start of voriconazole. The most common initial symptom was diffuse skeletal pain (68.28%) which can be severe and even disabling (66.7%). Ribs (37.21%), femurs (32.56%), scapulae (25.58%), humerus (23.26%), and clavicle (23.26%) were the common involved locations. Most cases were accompanied by different degrees of elevated serum alkaline phosphatase and fluoride level, while some presented with elevated bone-specific alkaline phosphatase. The main radiological features included periosteal reaction and multifocal high radiotracer uptake on bone scintigraphy. The formation of new bone was characterized with bilateral, irregular, nodular, as well as high density. The resolution of symptoms was observed with discontinuation of voriconazole in all patients, of whom 18 patients (52.94%) were relieved within a week. Itraconazole, posaconazole or isavuconazole were safe alternatives to voriconazole in voriconazole-induced periostitis. CONCLUSION: Voriconazole-induced periostitis is an infrequent complication characterized by bone inflammation involving one or multiple skeletal areas. Bony pain, elevated serum alkaline phosphatase as well as fluoride level are suspicious signs during voriconazole treatment.

Venetoclax ramp-up with concurrent voriconazole in a patient with chronic lymphocytic leukemia.

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is commonly treated with the B-cell lymphoma 2 inhibitor (BCL-2) venetoclax. Venetoclax is associated with an increased risk of tumor lysis syndrome in this patient population. Because venetoclax undergoes CYP3A4 metabolism, strong CYP3A4 inhibitors are contraindicated during the ramp-up phase of venetoclax in patients with CLL. CASE REPORT: Our case report describes a 58 year old male initially diagnosed with CLL in 2013, whose first-line treatment consisted of ibrutinib. The patient developed a central nervous system (CNS) aspergillosis infection in 2018, and was initiated on voriconazole. He was subsequently under active surveillance until his disease progressed. The patient was started on venetoclax therapy, while on concomitant voriconazole, for management of his CLL. MANAGEMENT AND OUTCOME: The patient's initial venetoclax dose was 10 mg daily, and he received rasburicase on day 1 of therapy. He tolerated a modified ramp-up phase without complication. After receiving 9 days of inpatient therapy, the patient was discharged on 50 mg of venetoclax to continue outpatient dose escalation. His dose was ultimately escalated to 100 mg daily. DISCUSSION: Although this report describes the safe administration of venetoclax with voriconazole, extreme caution should be exercised when administering venetoclax with any strong CYP3A4 inhibitor during the ramp-up phase in patients with CLL.

Papilledema and idiopathic intracranial hypertension due to the possible potentiation of ATRA by posaconazole in a case of acute promyelocytic leukemia.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) (pseudotumor cerebri) is a rare side effect of all-trans retinoic acid (ATRA). IIH cases have been observed after the concomitant use of ATRA with azole group antimicrobials such as fluconazole and voriconazole. Here, we discuss about the diagnosis and treatment process of the IIH emerging in a young acute promyelocytic leukemia (APL) case with the ATRA impact, which can be increased by posaconazole. CASE: A 19-year-old male patient was diagnosed with APL. Headache and blurred vision were developed on the 12th day of the AIDA (ATRA, 45 mg/m2/day, oral and idarubicin 12 mg/m2, on days 2, 4, 6, 8, intravenous) protocol and posaconazole proflaxis. He was diagnosed IIH along with the existing eye findings and imagings. MANAGEMENT & OUTCOME: ATRA treatment and posaconazole were interrupted. Systemic acetazolamide and dexamethasone treatment were initiated. After significant clinical response was observed, ATRA treatment was resumed without posaconazole and a similar clinical condition did not recur. DISCUSSION: The combined use of ATRA and azole group drugs increases the risk of developing IIH. Patients with APL who developed IIH during the concomitant use of ATRA and fluconazole or voriconazole have been reported. To the best of our knowledge, our case is the first APL case with a IIH who treated with ATRA-based therapy and used posaconazole. In case of development of side effects, drugs should be interrupted and this combination should be avoided if possible after appropriate approach and clinical improvement.

Use of Modeling and Simulation to Predict the Influence of Triazole Antifungal Agents on the Pharmacokinetics of Crizotinib.

Crizotinib is used for the treatment of c-ros oncogene 1-positive advanced non-small-cell lung cancer. Triazole antifungal agents are widely used for invasive fungal infections in clinical practice. To predict the potential influence of different triazoles (voriconazole, fluconazole, and itraconazole) on the pharmacokinetics of crizotinib by modeling and simulation the physiologically based pharmacokinetic models were established and validated in virtual cancer subjects through Simcyp software based on the essential physicochemical properties and pharmacokinetic data collected. The validated physiologically based pharmacokinetic models were applied to predict the drug-drug interactions between crizotinib and different triazoles (voriconazole, fluconazole, or itraconazole) in patients with cancer. Crizotinib and triazole antifungal agents were administered orally. The predicted plasma concentration vs time profiles of crizotinib, voriconazole, fluconazole, and itraconazole showed good agreement with observed, respectively. The geometric mean area under the plasma concentration-time curve (AUC) of crizotinib was increased by 84%, 58%, and 79% when coadministered with voriconazole, fluconazole, or itraconazole at multiple doses, respectively. The drug-drug interaction results showed increased pharmacokinetic exposure (maximum plasma concentration and area under the plasma concentration-time curve) of crizotinib when coadministrated with different triazoles (voriconazole > itraconazole > fluconazole). Among the 3 triazoles, voriconazole exhibited the most significant influence on the pharmacokinetic exposure of crizotinib. In clinic, adverse drug reactions and toxicity related to crizotinib should be carefully monitored, and therapeutic drug monitoring for crizotinib is recommended to guide dosing and optimize treatment when coadministered with voriconazole, fluconazole, or itraconazole.

Dementia-Like Symptoms Associated With Posaconazole.

Posaconazole is widely used in lung transplant recipients as pre-emptive therapy or universal fungal prophylaxis. In this patient group, posaconazole is increasingly used instead of voriconazole due to the concerns of an increased risk of squamous cell carcinoma (SCC) with voriconazole, particularly with its long-term use. Dose dependent toxicity has not been identified for posaconazole in the registration trials of intravenous (IV) and modified-release tablet formulations. This is supported by post-marketing experience. We describe a lung transplant recipient who experienced dementia-like symptoms almost 3 years after commencing posaconazole for treatment of Aspergillus fumigatus complex and Lomentospora prolificans (formerly Scedosporium prolificans) fungal infections. Symptoms resolved upon discontinuation of posaconazole, but recurred when re-challenged at a lower dose more than a year later. To the best of our knowledge, this is the first case reporting a dementia-like state with posaconazole.

Voriconazole Induced Ocular Surface Dysplasia - Report of Two Cases.

PURPOSE: To report ocular surface dysplasia induced by voriconazole treatment in two patients with recalcitrant fungal keratitis. METHODS: Observational study. RESULTS: Case 1 - A 49 year old female who was a known case of fungal keratitis and treated with prolonged topical voriconazole therapy, underwent penetrating keratoplasty and the histopathological examination of corneal specimen showed multiple keratin pearls with dyskeratotic cells suggestive of squamous cell carcinoma.Case 2 - A 78-year-old man who was diagnosed as fungal keratitis in his left eye and treated with topical voriconazole 1% and itraconazole 1% for 6 months underwent therapeutic penetrating keratoplasty. Histopathology of the host corneal tissue showed squamous cells with irregular thickening with dyskeratotic cells and squamous eddies suggestive of voriconazole induced dysplasia. CONCLUSION: Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia. Early diagnosis and treatment of the dysplastic changes can result in complete remission and prevent recurrence.

A case of acute pancreatitis induced by voriconazole during treatment of cryptococcal meningitis.

Acute pancreatitis refers to pancreatic enzyme activation caused by a variety of aetiologies, and mainly characterized by local inflammation of the pancreas, with or without diseases of other organ function changes. The main clinical features are abdominal pain and elevated trypsin levels in the blood. Common causes of acute pancreatitis include cholelithiasis, alcohol consumption and hyperlipidaemia, among which drugs are considered to be one of the rare causes of pancreatitis. The patient in this case was a 16-year-old adolescent female who developed acute severe pancreatitis during the treatment of cryptococcal meningitis with voriconazole for 35 days. Following diagnosis that pancreatitis was induced by voriconazole, the drug was immediately stopped and the patient was discharged after symptomatic treatment. The phenomenon of voriconazole-induced pancreatitis is extremely rare, but we hope that this report can arouse greater attention and vigilance of the majority of medical personnel to improve the safety of patients' medication, especially for children or minors.

Formulation, optimization, and nephrotoxicity evaluation of an antifungal in situ nasal gel loaded with voriconazole‒clove oil transferosomal nanoparticles.

Fungal infections of the paranasal cavity are among the most widely spread illnesses nowadays. The aim of the current study was to estimate the effectiveness of an in situ gel loaded with voriconazole‒clove oil nano-transferosomes (VRC-CO-NT) in enhancing the activity of voriconazole against Aspergillus flavus, which causes rhinosinusitis. The nephrotoxic side effects of voriconazole may be reduced through the incorporation of the clove oil, which has antioxidant activity that protects tissue. The Box‒Behnken design was applied to formulate the VRC-CO-NT. The particle size, entrapment efficiency, antifungal inhibition zone, and serum creatinine concentration were considered dependent variables, and the soybean lecithin, VRC, and CO concentrations were considered independent ones. The final optimized formulation was loaded into a deacetylated gellan gum base and evaluated for its gelation, rheological properties, drug release profile, permeation capabilities, and in vivo nephrotoxicity. The optimum formulation was determined to be composed of 50 mg/mL lecithin, 18 mg/mL VRC, and 75 mg/mL CO, with a minimum particle size of 102.96 nm, an entrapment efficiency of 71.70%, an inhibition zone of 21.76 mm, and a serum creatinine level of 0.119 mmol/L. The optimized loaded in situ gel released 82.5% VRC after 12 hours and resulted in a 5.4-fold increase in drug permeation. The in vivo results obtained using rabbits resulted in a nonsignificant differentiation among the renal function parameters compared with the negative control group. In conclusion, nasal in situ gel loaded with VRC-CO-NT is considered an efficient novel carrier with enhanced antifungal properties with no signs of nephrotoxicity.