Abstract
Invasive Pulmonary Aspergillosis (IPA) and Pneumocystis jiroveci Pneumonia (PCP) are serious fungal pulmonary diseases for immunocompromised patients. The brand name drug CANCIDAS® (Caspofungin acetate for injection) is FDA approved to treat IPA, but is only 40% effective. Efficacious drug levels at the lung infection site are not achieved by systemic administration. Increasing the dose leads to toxicity. The objective, here, is to reformulate caspofungin for aerosolization to high drug concentration by lung targeted delivery and avoid systemic distribution. Described in this paper is a new, room temperature-stable formulation that meets these goals. The in vitro antifungal activity, solid state and reconstituted stability, and aerosol properties of the new formulation are presented. In addition, pharmacokinetic parameters and tissue distribution data are determined from nose-only inhalation studies in rats. Plasma and tissue samples were analyzed by High Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC-MS-MS). Inhaled drug concentrations for caspofungin Active Pharmaceutical Ingredient (API), and the new formulation, were compared at the same dose. In the lungs, the parameters Cmax and Area Under Curve (AUC) showed a 70%, and 60%, respective increase in drug deposition for the new formulation without significant systemic distribution. Moreover, the calculated pharmacodynamic indices suggest an improvement in efficacy. These findings warrant further animal toxicology studies and human clinical trials, with inhaled caspofungin, for treating IPA.
Highlights
IntroductionFungal pulmonary infections, caused by Aspergillus or Pneumocystis jiroveci, are serious diseases that devastate immunocompromised patients who receive chemotherapy or immunosuppressive agents, associated with their illness, as well as HIV patients
CANCIDAS® was reconstituted per label instructions and caspofungin Active Pharmaceutical Ingredient (API) was dissolved in normal saline
Testing against the Candida spp., Aspergillus fumigatus and Trichophyton rubrum showed that the new formulations, TTI-016 and TTI-017, retain antifungal activity comparable to that of CANCIDAS® and the presence of formulation excipients does not interfere with antifungal activity (Table 1)
Summary
Fungal pulmonary infections, caused by Aspergillus or Pneumocystis jiroveci, are serious diseases that devastate immunocompromised patients who receive chemotherapy or immunosuppressive agents, associated with their illness, as well as HIV patients. Ubiquitous airborne spores are inhaled and become established in the lung [1]. Alveolar macrophages in the lung remove these spores efficiently. Patients with compromised immune systems, due to chemotherapy or immunosuppressive agents, cannot eradicate spores like healthy individuals. Aspergillus propagates very rapidly in these patients’ lungs. The overall case fatality rate, even with the treatment, can reach 86% in bone marrow transplant patients [3]. Despite the high mortality of Aspergillus infections, current systemic IPA treatments only provide modest efficacy for all patients averaging between 40–50%
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