Pulmonary delivery of aqueous voriconazole solution



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Invasive Pulmonary Apsergillosis (IPA) is caused by inhalation of fungal conidia to the deep lung followed by germination and invasive hyphal growth in heavily immunosuppressed patients (e.g. those with hematologic malignancies, hematopoietic stem cell transplant recipients, and those undergoing solid organ transplantation). Hyphal growth into pulmonary capillaries often leads to dissemination of the infection and high mortality rates despite current treatment and prophylactic modalities. In addition, systemic antifungal therapy is often limited by drug toxicities, low and variable bioavailability, erratic pharmacokinetics, and drug interactions. Although targeted drug delivery to the lungs has been investigated to reduce adverse events and promote drug efficacy, inconsistent pharmacokinetic properties following inhalation of poorly water soluble antifungals has prompted variable drug efficacy. In this dissertation, inhaled voriconazole was investigated through in vitro and in vivo testing to evaluate pharmacokinetic properties, characterize drug safety and, determine drug efficacy as prophylaxis against IPA. In Chapter 2, the in vitro evaluation of solution properties and aerosol characterization of aqueous voriconazole was evaluated. Subsequent in vivo single and multiple dose pharmacokinetic studies demonstrated high drug concentrations were achieved in lung tissue and plasma following inhalation in contrast to previous reports of inhaled antifungals. Inhaled voriconazole was then administered twice daily (BID, at 08:00 and 16:00) in a murine model of IPA as described in Chapter 3 with significant improvements in animal survival over 12 days compared to both positive and negative control groups. As described in Chapter 4, voriconazole was then chronically administered BID at a high and low dose to rats over 21 days with a 7 day recovery period to assess dose tolerability through laboratory tests and histopathological changes to lung, liver, kidney, and spleen tissues. Inhaled voriconazole was well tolerated through all assessments but with signs of mild acute histiocytosis in lung tissue without other signs of inflammation. Chapter 5 expanded the single inhaled dose pharmacokinetic profile in lung tissue and plasma with determination of additional pharmacokinetic parameters through compartmental modeling. Peak and trough voriconazole concentrations were also evaluated in mice as well as rats following multiple doses administered over 12 hours (Q12H) as opposed to BID.