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Published on: March 9, 2018
Assessment and Development of the Antifungal Agent Caspofungin for Aerosolized Pulmonary Delivery
Iching G Yu1, David M Ryckman1
1Trilogy Therapeutics, Inc., San Diego, CA 92130, USA.
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.
Insights
A new inhaled caspofungin formulation enhances drug delivery to the lungs for treating invasive pulmonary aspergillosis (IPA). This targeted approach improves efficacy and reduces systemic exposure compared to standard intravenous administration.
Area of Science:
- Pulmonary Medicine
- Pharmaceutical Sciences
- Drug Delivery Systems
Background:
- Invasive Pulmonary Aspergillosis (IPA) and Pneumocystis jiroveci Pneumonia (PCP) are severe fungal infections in immunocompromised individuals.
- Current systemic treatment with caspofungin (CANCIDAS®) has limited efficacy (40%) due to inadequate drug levels at the lung infection site and potential toxicity with dose escalation.
Purpose of the Study:
- To develop and characterize a novel, room temperature-stable, aerosolized formulation of caspofungin for targeted lung delivery.
- To evaluate the in vitro and in vivo performance of the new formulation, focusing on efficacy and reduced systemic distribution.
Main Methods:
- Formulation of aerosolizable caspofungin.
- Assessment of in vitro antifungal activity, stability (solid-state and reconstituted), and aerosol properties.
- In vivo pharmacokinetic and tissue distribution studies using nose-only inhalation in rats.
- Quantification of caspofungin in plasma and tissues via HPLC-MS-MS.
Main Results:
- The new formulation demonstrated room temperature stability and suitable aerosol properties.
- Inhalation studies in rats showed a 70% increase in Cmax and a 60% increase in AUC for lung caspofungin deposition compared to the API alone at the same dose.
- Significantly reduced systemic distribution was observed with the new formulation.
- Calculated pharmacodynamic indices suggest improved efficacy.
Conclusions:
- A novel inhaled caspofungin formulation achieves high drug concentrations in the lungs with minimal systemic exposure.
- This targeted delivery approach holds promise for improving treatment outcomes for invasive pulmonary aspergillosis.
- Further preclinical toxicology and human clinical trials are warranted.
