Interactions With Azole Antifungal Agents in Transplant Recipients
Interactions With Azole Antifungal Agents in Transplant Recipients
Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966–December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity). These aspects of drug interaction management are essential not only at the initiation of azole antifungal therapy, but also when these agents are removed from the regimen.
Invasive fungal infections represent a major challenge in hematopoietic stem cell transplant (HSCT) and solid organ transplant recipients. Because of the high rates of morbidity and mortality in these patient populations, effective prevention and/or treatment of invasive fungal infections is critical. Because azole antifungals are available for oral and, in most cases, intravenous administration, they can easily be used in both the inpatient and ambulatory settings, providing a pharmacologic option for the long duration of therapy needed for prophylaxis or treatment of invasive disease. However, as a result of their primary mechanism of antifungal activity, all of these agents potentially interfere with metabolism and transport of the immunosuppressive regimens that are required to prevent rejection and graft-versus-host disease (GVHD) in the solid organ transplant and HSCT populations, respectively.
Interactions involving azole antifungal agents are common. A retrospective cohort analysis of 3353 patients who had 4185 admissions in which fluconazole (3953 admissions [94.5%]), itraconazole (212 [5.1%]), or ketoconazole (68 [1.6%]) were administered during their hospitalization found that potential azole-related drug interactions occurred in 70.3% of admissions. Potential azole-related drug interactions were reported in 68.7% of fluconazole-treated, 95.8% of itraconazole-treated, and 88.2% of ketoconazole-treated patients.
The transplant team needs to be aware of these drug interactions and know how to manage them. To identify drug interactions that may result between azole antifungals and other drugs commonly used in the transplant setting, we conducted a literature search of the MEDLINE database (1966–December 2009) for English-language articles on drug interaction studies involving azole antifungal agents. The following key words were used: fluconazole, itraconazole, voriconazole, posaconazole, and drug interactions. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids, methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Guidance on safe administration of azoles to transplant recipients, including management of drug interactions and recommendations for monitoring of drug concentrations and clinical course, is also provided. Although this review focuses on interactions between azoles and drugs commonly used in transplant recipients, it is not an exhaustive review of all potential drug interactions with azole antifungals.
Abstract and Introduction
Abstract
Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966–December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity). These aspects of drug interaction management are essential not only at the initiation of azole antifungal therapy, but also when these agents are removed from the regimen.
Introduction
Invasive fungal infections represent a major challenge in hematopoietic stem cell transplant (HSCT) and solid organ transplant recipients. Because of the high rates of morbidity and mortality in these patient populations, effective prevention and/or treatment of invasive fungal infections is critical. Because azole antifungals are available for oral and, in most cases, intravenous administration, they can easily be used in both the inpatient and ambulatory settings, providing a pharmacologic option for the long duration of therapy needed for prophylaxis or treatment of invasive disease. However, as a result of their primary mechanism of antifungal activity, all of these agents potentially interfere with metabolism and transport of the immunosuppressive regimens that are required to prevent rejection and graft-versus-host disease (GVHD) in the solid organ transplant and HSCT populations, respectively.
Interactions involving azole antifungal agents are common. A retrospective cohort analysis of 3353 patients who had 4185 admissions in which fluconazole (3953 admissions [94.5%]), itraconazole (212 [5.1%]), or ketoconazole (68 [1.6%]) were administered during their hospitalization found that potential azole-related drug interactions occurred in 70.3% of admissions. Potential azole-related drug interactions were reported in 68.7% of fluconazole-treated, 95.8% of itraconazole-treated, and 88.2% of ketoconazole-treated patients.
The transplant team needs to be aware of these drug interactions and know how to manage them. To identify drug interactions that may result between azole antifungals and other drugs commonly used in the transplant setting, we conducted a literature search of the MEDLINE database (1966–December 2009) for English-language articles on drug interaction studies involving azole antifungal agents. The following key words were used: fluconazole, itraconazole, voriconazole, posaconazole, and drug interactions. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids, methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Guidance on safe administration of azoles to transplant recipients, including management of drug interactions and recommendations for monitoring of drug concentrations and clinical course, is also provided. Although this review focuses on interactions between azoles and drugs commonly used in transplant recipients, it is not an exhaustive review of all potential drug interactions with azole antifungals.
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