Laboratory training and experience for an undergraduate

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PROJECT SUMMARY There is an urgent need for the development of approaches to prevent cardiotoxicity in cancer patients being treated with anthracyclines, an important class of drugs in the treatment of cancer (e.g. doxorubicin). Anthracycline treatment-related cardiotoxicity is a major clinical problem that severely impacts patient care and also limits dose and usage. More than a quarter of patients who receive doxorubicin develop significant cardiac morbidity, and this effect has been shown to be dose dependent. In multiple preclinical studies, we and others have defined the therapeutic potential of low-dose exogenous carbon monoxide (CO) in anthracycline cardiotoxicity prevention, including protecting the cardiomyocyte from cell death and maintaining overall cardiovascular health. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies carried out to study the potential benefit of CO. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO release characteristics that have proven to be a substantial barrier to development. HBI-002, the novel oral CO drug product, was developed to overcome these barriers and enable the use of CO to prevent cardiotoxicity from anthracycline use. As with all drugs, the assessment of the concentration of the active pharmaceutical ingredient (API) in tissue of interest is critical. Although data exist in tissue with inhaled CO, no data exist with HBI-002, and the data with inhaled CO may not be applicable given the typically high doses of iCO that are given in tissue distribution studies. For these reasons, the objective of the proposed project is to determine tissue levels and pharmacokinetics of CO exposure after oral HBI-002 drug product dosing.