isavuconazole and Graft-vs-Host-Disease

Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.

Topics: Adult; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; DNA, Fungal; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Nitriles; Pyridines; Thorax; Transplantation, Homologous; 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