tacrolimus and isavuconazole

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 → 3)-β-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.

Topics: Acute Kidney Injury; Administration, Inhalation; Amphotericin B; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antifungal Agents; Azithromycin; Ceftriaxone; COVID-19; Deprescriptions; Female; Glucocorticoids; Graft Rejection; Humans; Hydroxychloroquine; Hyperoxaluria, Primary; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Invasive Pulmonary Aspergillosis; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Nitriles; Oxygen Inhalation Therapy; Prednisone; Pyridines; Renal Dialysis; SARS-CoV-2; Sputum; Tacrolimus; Tomography, X-Ray Computed; Triazoles

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration-time curves (AUC

Topics: Adult; Area Under Curve; Cyclosporine; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Middle Aged; Mycophenolic Acid; Nitriles; Prednisolone; Pyridines; Sirolimus; Tacrolimus; Triazoles; Young Adult

Isavuconazole has theoretical advantages over other mold-active triazoles for the treatment of invasive aspergillosis and mucormycosis after solid organ transplantation (SOT). The available clinical experience, nevertheless, is scarce.. We performed a retrospective study including all adult SOT recipients with proven or probable invasive mold disease (IMD) that received isavuconazole for ≥24 h as first-line or salvage therapy at 10 Spanish centers between September 2017 and November 2021. The primary efficacy outcome was clinical response (complete or partial resolution of attributable symptoms and findings) by weeks 6 and 12. Safety outcomes included the rates of treatment-emergent adverse events and premature isavuconazole discontinuation.. We included 81 SOT recipients that received isavuconazole for a median of 58.0 days because of invasive aspergillosis (n = 71) or mucormycosis (n = 10). Isavuconazole was used as first-line (72.8%) or salvage therapy due because of previous treatment-emergent toxicity (11.1%) or refractory IMD (7.4%). Combination therapy was common (37.0%), mainly with an echinocandin or liposomal amphotericin B. Clinical response by weeks 6 and 12 was achieved in 53.1% and 54.3% of patients, respectively, and was more likely when isavuconazole was administered as first-line single-agent therapy. At least 1 treatment-emergent adverse event occurred in 17.3% of patients, and 6.2% required premature discontinuation. Daily tacrolimus dose was reduced in two-thirds of patients by a median of 50.0%, although tacrolimus levels remained stable throughout the first month of therapy.. Isavuconazole is a safe therapeutic option for IMD in SOT recipients, with efficacy comparable to other patient groups.

Topics: Adult; Antifungal Agents; Aspergillosis; Fungi; Humans; Invasive Fungal Infections; Mucormycosis; Nitriles; Organ Transplantation; Retrospective Studies; Tacrolimus; Transplant Recipients; Triazoles

Limited evidence exists on the effect of isavuconazonium sulfate and posaconazole delayed release tablets on tacrolimus dose-to-concentration ratios in lung transplant recipients.. The purpose of this evaluation was to assess the impact of novel triazoles on tacrolimus dose-to-concentration ratios.. This retrospective review included lung transplant recipient ≥18 years of age from January 1, 2017 to October 1, 2020 who received either posaconazole delayed release tablets or isavuconazonium sulfate for. A paired analysis evaluated outcomes pre-triazole and post-triazole initiation.. Forty-one patients met evaluation criteria for inclusion. A total of 34 of 41 patients received posaconazole delayed release tablets. Of these patients, 22 of 34 were transitioned from previous triazole to posaconazole delayed release tablets and experienced a 47% reduction in tacrolimus dose-to-concentration ratio. Twelve patients were newly initiated on posaconazole delayed release tablets and experienced a 50% reduction in tacrolimus dose-to-concentration ratios. Although not statistically significant, a 30% reduction in tacrolimus dose-to-concentration ratio was observed when transitioning to isavuconazonium sulfate from previous triazole therapy.. Limited data exists to provide guidance on tacrolimus dose adjustments with initiation and conversion of novel triazoles, however, this evaluation provides more knowledge on the drug interaction with novel triazoles and tacrolimus.

Topics: Antifungal Agents; Humans; Tablets; Tacrolimus; Triazoles

Because tacrolimus has a narrow therapeutic window and exhibits both intraindividual and interindividual variability, we attempted to establish the percentage of calcineurin inhibitor (CNI) dose reduction to prevent toxicity and ensure stem cell engraftment when using this immunosuppressant with the antifungal isavuconazole (ISA). By calculating the tacrolimus concentration/dose (C/D) ratio, we expected to demonstrate the magnitude of change in the C/D ratio from baseline after ISA administration.. We evaluated the interaction between ISA, a new triazole antifungal used in prophylaxis for invasive fungal infections, and the CNI class of immunosuppressive drugs, specifically tacrolimus, in 11 blood samples from HSCT recipients.. The mean tacrolimus C/D ratio increased 1.44-fold from baseline 48 h after ISA administration (P = 0.001).. Although further investigation is needed, the results of this study suggest that a reduction of 18% in tacrolimus may be recommended.

Topics: Antifungal Agents; Drug Interactions; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Tacrolimus; Triazoles

Calcineurin inhibitors are commonly used in hematopoietic stem cell transplant (HSCT) patients to prevent graft versus host disease, but as CYP3A4 substrates they are frequently involved in drug-drug interactions. The purpose of this study is to characterize the effects of isavuconazole, fluconazole, and posaconazole on tacrolimus and cyclosporine serum concentrations and dose adjustments in allogeneic HSCT patients.. This retrospective study included patients admitted to Oregon Health and Science University between April 2008 and December 2018 who underwent hematopoietic stem cell transplantation and received concomitant tacrolimus or cyclosporine and fluconazole, isavuconazole or posaconazole therapy. Data on patient characteristics, drug dosing, and serum drug concentrations were collected through chart review, and descriptive statistics were used to summarize the results.. A total of 139 patients were included in this study. We found fluconazole initiation leads to a 25% reduction in both tacrolimus and cyclosporine doses in order to maintain goal serum concentrations. Posaconazole and isavuconazole initiation requires tacrolimus dose reductions by 53% and 21%, respectively.. Based on our experience, FLC, POS, and ISA initiation may require CNI dose reductions and close monitoring of CNI levels to ensure levels remain within goal serum concentrations. Larger studies are needed to fully quantify the percentage in CNI dose reductions and characterize differences among these antifungals.

Topics: Antifungal Agents; Cyclosporine; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Nitriles; Pyridines; Retrospective Studies; Tacrolimus; Triazoles

A paucity of data currently exists regarding drug-drug interaction (DDI) with tacrolimus and isavuconazole coadministration. Current literature provides conflicting recommendations on whether an empiric tacrolimus dose reduction is necessary when coadministered with isavuconazole. A 47-year-old African American female with acute lymphoblastic leukemia underwent an allogenic stem cell transplant (alloSCT) and was subsequently placed on routine posttransplant therapy including tacrolimus for immunosuppression and posaconazole for antifungal prophylaxis. Tacrolimus was empirically dose reduced due to the expected DDI with posaconazole based on current recommendations. Due to a persistently prolonged QTc interval and need for mold coverage, antifungal prophylaxis was ultimately changed to isavuconazole at standard recommended dosing. Tacrolimus was empirically dose reduced by 40% based on limited available literature at the time; however, tacrolimus trough concentrations subsequently declined, requiring an increase in tacrolimus dose to maintain therapeutic trough concentrations. Adequate isavuconazole absorption was documented through pharmacokinetic and pharmacodynamic data by measuring an isavuconazole trough concentration and directly observing isavuconazole's shortening effect on the QTc interval, respectively. Our experience in an alloSCT patient suggests that an empiric tacrolimus dose reduction is not required when isavuconazole is initiated, but close tacrolimus therapeutic drug monitoring should rather be performed to guide tacrolimus dosing.

Topics: Allografts; Antifungal Agents; Drug Interactions; Drug Monitoring; Drug Tapering; Female; Humans; Immunosuppressive Agents; Middle Aged; Nitriles; Pyridines; Tacrolimus; Triazoles

Isavuconazole, a triazole antifungal, is an inhibitor of cytochrome P450 3A4, which also metabolizes tacrolimus and sirolimus. In previous studies, isavuconazole administration increased tacrolimus and sirolimus area under the curve values by 2.3-fold and 1.8-fold, respectively, in healthy adults and tacrolimus concentration/dose (C/D) ratio by 1.3-fold in solid organ transplant patients. We aimed to determine the magnitude of effect of isavuconazole administration on tacrolimus and sirolimus C/D ratios in allogeneic hematopoietic stem cell transplant (alloHSCT) patients.. A retrospective, single-center, single-arm study in adult alloHSCT patients who received at least 10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus as inpatients or outpatients was conducted. Tacrolimus and sirolimus trough serum concentrations were measured up to twice weekly for up to 4 weeks.. Twenty-two patients receiving tacrolimus and twenty patients receiving sirolimus met the inclusion criteria. The mean C/D ratio increased from baseline by 1.42-fold for tacrolimus during week 1 (P = 0.002) and up to 1.56-fold for sirolimus during week 2 (P = 0.02). For the remaining timepoints, tacrolimus and sirolimus C/D ratios were not statistically significantly different from baseline.. In alloHSCT patients, modest increases in tacrolimus and sirolimus C/D ratios from baseline were observed within the first 2 weeks after initiation of isavuconazole.

Topics: Adult; Aged; Antifungal Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Nitriles; Pyridines; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation, Homologous; Triazoles; Young Adult

To evaluate the in vitro interactions of isavuconazole with immune suppressors (tacrolimus, cyclosporin A or sirolimus) against 30 Mucorales isolates belonging to the most common species responsible for mucormycosis in humans (Rhizopus arrhizus, Rhizopus delemar, Rhizopus microsporus, Lichtheimia corymbifera, Lichtheimia ramosa, Mucor circinelloides and Rhizomucor pusillus).. In vitro interaction was evaluated by a microdilution chequerboard technique.. Combination of isavuconazole with tacrolimus, cyclosporin A or sirolimus, was synergistic for 50%, 46% and 7% of the isolates, respectively. Antagonistic interaction was observed for 4% of the isolates for the combination with cyclosporin A (one R. arrhizus isolate) and for 32% of the isolates for the combination with sirolimus (six R. arrhizus isolates and three R. pusillus isolates).. These in vitro data show that calcineurin inhibitors are more likely than inhibitors of the mTOR pathway to enhance the activity of isavuconazole against Mucorales. These in vitro results warrant further animal experiments.

Topics: Antifungal Agents; Cyclosporine; Immunosuppressive Agents; Microbial Sensitivity Tests; Mucorales; Mucormycosis; Nitriles; Pyridines; Sirolimus; Tacrolimus; Triazoles

We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.

Topics: Adult; Aged; Antifungal Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Middle Aged; Nitriles; Pyridines; Retrospective Studies; Tacrolimus; Transplant Recipients; Triazoles; Young Adult