Novel clinical assay to rapidly monitor posaconazole levels in plasma

SUMMARY/ABSTRACT 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.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.