LAS VEGAS — An inhaled formulation of amphotericin B, currently in development, may fill the need for antifungal prophylaxis in immunocompromised patients, according to Michael J. Weickert, Ph.D.
Regimens that protect against bacterial, viral, and yeast infections are widely used for patients undergoing chemotherapy to prepare for bone marrow or stem cell transplantation, to prevent rejection of a solid organ transplant, to treat hematologic malignancy, or to control graft vs. host disease.
These patients—of whom about 150,000 reside in the United States and Europe—remain susceptible to infections with molds such as Aspergillus fumigatus, and mortality is high, reportedly between 44% and 87%.
To meet the need for antifungal prophylaxis, a dry powder aerosol formulation of amphotericin B has been developed, and a multidose clinical study is underway, said Dr. Weickert, an employee and shareholder in Nektar Therapeutics, the manufacturer.
The powder is packed into a capsule that is inserted into a small pulmonary delivery device. The drug is delivered to the lungs in a single inhalation, and because the particles have the same aerodynamic properties as fungal spores, they distribute to the same sites that the spores would if inhaled, Dr. Weickert explained at a meeting on fungal infections sponsored by Imedex.
In the regimens being tested, a loading dose is given on day 0 that would achieve a concentration of the drug in the lung that is many times higher than the minimum inhibitory concentration (MIC) required during the early, high-risk period for colonization and infection with Aspergillus.
The loading dose is followed by a lower maintenance dose, self-administered weekly to maintain adequate MIC long term.
Systemic levels of the drug are expected to be very low, and the hope is that the toxicities that have long prevented the use of intravenous amphotericin B prophylactically will be avoided, he said.
The drug has been tested in doses of 5 mg, 10 mg, and 25 mg. For the 25-mg dose, the peak systemic level of the drug was 20 ng/mL, which is about 2% of the level generally regarded as the threshold of toxicity for amphotericin B, Dr. Weickert said.
Adverse events, such as cough, headache, and taste distortions have been seen, but these were not serious. “In general [amphotericin B] has been very well tolerated.”
The product received orphan drug designation on Dec. 15, 2005, and a phase III trial should begin next year.