Aerosol amphotericin B in the works as fungal prophylaxis.

LAS VEGAS -- An inhaled formulation of amphotericin B in clinical development may answer the unmet need for antifungal prophylaxis in immunocompromised patients, said 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, prevent rejection of a solid organ transplant, treat hematologic malignancy, or control graft vs. host disease.

These patients--about 150,000 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, who is an employee of 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 during a single inhalation. The particles, which have the same aerodynamic properties as fungal spores, 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 zero that would achieve a concentration of the drug in the lung 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 that is self-administered at weekly intervals to maintain an adequate MIC long term, he said.

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, were not serious. "In general [amphotericin B] has been very well tolerated," he said.

The product received orphan drug designation on Dec. 15, 2005, and a phase III trial is expected to begin within the next year.


New York Bureau

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