Invasive fungal infections (IFIs) contribute to more than 1.5 million deaths worldwide each year and pose a serious and continuous health risk to immunocompromised individuals. The rate of mortality associated with IFI is high, and there are only four major classes of antifungal drugs available to treat IFI, of which the triazoles find greatest use. Posaconazole (PCZ; Noxafil®) is the newest triazole and is the broadest spectrum, demonstrating activity against Aspergillus, Candida and Cryptococcus species. PCZ is indicated in the U.S. for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk for these infections, including hematopoietic stem cell transplant recipients, those with hematologic malignancies, and other immunocompromised patients. It is also indicated for treatment of oropharyngeal candidiasis (OTC), a condition common among HIV patients. While PCZ is not associated with significant toxicities, it displays high inter- and intra-individual variation in plasma drug concentrations, with subtherapeutic levels associated with poor efficacy. There is significant evidence to demonstrate that inadequate exposure to antifungals is independently associated with increased hospital mortality, and the Infectious Diseases Society of America recommends therapeutic drug monitoring (TDM) of PCZ to ensure adequate treatment. Unfortunately, there are currently no FDA approved assays available for performing PCZ TDM. Available assays remain limited to institutions or laboratories that have developed in-house laboratory-developed tests that rely on high- performance liquid chromatography (HPLC) or HPLC with mass spectrometry. These complex assays are expensive and lack harmonization, making it impossible to compare results from one test to the next. Most importantly, the turnaround time can range from several days to a week, making routine dose adjustments based on timely results impossible. Affinergy plans to develop a novel locking assay for the direct measurement of PCZ levels in plasma that is compatible with common clinical chemistry analyzers to facilitate routine TDM. Our assay with its lower cost and rapid turnaround will open access to a majority of patients to ensure that therapeutic levels are achieved to prevent life-threatening breakthrough infections and help control the rise of resistant strains. Public Health Relevance Statement PROJECT NARRATIVE Invasive fungal infections contribute to more than 1.5 million deaths worldwide each year and pose a serious and continuous health risk to immunocompromised individuals. Therapeutic drug monitoring of the triazole antifungal, posaconazole, is recommended to ensure effective therapy, prevent mortality, and limit the development of resistance. We propose to develop a novel assay that is compatible with common clinical chemistry analyzers to directly measure levels of posaconazole in plasma and facilitate therapeutic drug monitoring in routine care.
Project Terms: commercialization ; high risk ; FDA approved ; routine care ; effective therapy ; effective treatment ; resistant strain ; resistance strain ; verification and validation ; individual variation ; individual heterogeneity ; individual variability ; infection risk ; rapid test ; rapid assay ; rapid tests ; detection limit ; Adoption ; Americas ; Antifungal Agents ; Antifungal Drug ; Therapeutic Fungicides ; anti-fungal ; anti-fungal agents ; anti-fungal drug ; antifungals ; Aspergillus ; Bacteriophages ; Phages ; bacterial virus ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Buffers ; Candida ; Monilia ; Candida albicans ; C albicans ; C. albicans ; C.albicans ; Clinical Chemistry ; High Pressure Liquid Chromatography ; HPLC ; High Performance Liquid Chromatography ; High Speed Liquid Chromatography ; Communicable Diseases ; Infectious Disease Pathway ; Infectious Diseases ; Infectious Disorder ; Cryptococcus ; Torula ; Cytochrome P450 ; Cytochrome P-450 ; Cytochrome P-450 Enzyme System ; Cytochrome P450 Family Gene ; P450 ; Cessation of life ; Death ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Enzymes ; Enzyme Gene ; Health ; HIV ; AIDS Virus ; Acquired Immune Deficiency Syndrome Virus ; Acquired Immunodeficiency Syndrome Virus ; Human Immunodeficiency Viruses ; LAV-HTLV-III ; Lymphadenopathy-Associated Virus ; Virus-HIV ; Immobilization ; orthopedic freezing ; Infection ; Institutes ; Laboratories ; mortality ; Mycoses ; Fungus Diseases ; fungal infection ; fungus infection ; Patients ; Peptides ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; pressure ; Production ; Reagent ; Risk ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Societies ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Sterols ; Technology ; Testing ; Time ; Triazoles ; Sirolimus ; Rapamune ; Rapamycin ; Measures ; Immunocompromised Host ; Immunocompromised ; Immunocompromised Patient ; Immunosuppressed Host ; immunosuppressed patient ; Drug Monitoring ; Hospital Mortality ; In-house Mortalities ; Inhospital Mortality ; Guidelines ; base ; Prophylactic treatment ; Prophylaxis ; Clinical ; Phase ; Ensure ; Individual ; Measurement ; Hematopoietic Stem Cell Transplantation ; HSC transplantation ; Hematopoietic Stem Cell Transplant ; Therapeutic ; Exposure to ; transplant patient ; Transplant Recipients ; Hematologic Cancer ; Hematologic Malignancies ; Hematological Malignancies ; Hematological Neoplasms ; Hematological Tumor ; Hematopoietic Cancer ; Malignant Hematologic Neoplasm ; Hematologic Neoplasms ; Life ; Viread ; Tenofovir ; Complex ; Performance ; Toxicities ; Toxic effect ; novel ; validation studies ; Sampling ; Oropharyngeal Candidiasis ; oropharyngeal thrush ; peptide aminoacid sequence ; peptide sequence ; protein aminoacid sequence ; posaconazole ; Molecular Interaction ; Binding ; Institution ; preventing ; prevent ; magnetic beads ; reagent testing ; Dose ; Affinity ; Detection ; Endogenous Factors ; Phage Display ; Monitor ; Pathway interactions ; pathway ; Output ; cost ; scale up ; Resistance development ; Resistant development ; developing resistance ;
