SUBCUTANEOUSLY ADMINISTERED RECOMBINANT INTERFERON-GAMMA IN HUMANS - PHARMACOKINETICS AND EFFECTS ON CHEMILUMINESCENCE RESPONSES OF ALVEOLAR MACROPHAGES, BLOOD NEUTROPHILS, AND MONOCYTES

A Phase I trial was conducted to investigate the clinical toxicity, ph armacokinetics, and chemiluminescence (CL) responses of alveolar macro phages (AMs), peripheral blood neutrophils, and monocytes after subcut aneous injection of recombinant interferon-gamma (rIFN-gamma). Six pat ients with lung cancer received rlFN-gamma subcutaneously as single do ses of 0.2, 0.6, and 1.8 mg. Bronchoalveolar lavage was performed thre e times: 21 h before as well as 6-7 and 27 h after injection. Serum sa mples were taken five times during the 27-h follow-up. IFN concentrati ons were measured from alveolar epithelial lining fluid (ELF) and seru m by using an antiviral bioassay. IFN-gamma was not detectable in ELF after subcutaneous injection. AMs did not effect an increase in CL res ponses to N-formyl-methionyl-leucyl-phenylalanine or to phosphate-buff ered saline. Circulating IFN-gamma was detectable at 3-12 h after an i njection of 1.8 mg of rIFN-gamma, the highest dose given. CL responses of peripheral blood monocytes increased in all patients after injecti on, whereas the responses of neutrophils were less clear-cut. All pati ents developed systemic side effects such as transient fever, nausea, headaches, and flu-like symptoms. The findings suggest that rIFN-gamma passes poorly from the blood to the pulmonary alveoli. On the basis o f this and our previous findings of increased CL responses in AMs and measurable IFN concentrations in ELF after inhalation of rIFN-gamma, w e recommend inhalation rather than the parenteral route of IFN-gamma f or the treatment of respiratory diseases.