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, pharmacokinetics, and chemiluminescence (CL) responses of alveolar macrophages (AMs), peripheral blood neutrophils, and monocytes after subcutaneous injection of recombinant interferon-gamma (rIFN-gamma). Six patients with lung cancer received rIFN-gamma subcutaneously as single doses of 0.2, 0.6, and 1.8 mg. Bronchoalveolar lavage was performed three times: 21 h before as well as 6-7 and 27 h after injection. Serum samples were taken five times during the 27-h follow-up. IFN concentrations were measured from alveolar epithelial lining fluid (ELF) and serum by using an antiviral bioassay. IFN-gamma was not detectable in ELF after subcutaneous injection. AMs did not effect an increase in CL responses to N-formyl-methionyl-leucyl-phenylalanine or to phosphate-buffered saline. Circulating IFN-gamma was detectable at 3-12 h after an injection of 1.8 mg of rIFN-gamma, the highest dose given. CL responses of peripheral blood monocytes increased in all patients after injection, whereas the responses of neutrophils were less clear-cut. All patients 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 of this and our previous findings of increased CL responses in AMs and measurable IFN concentrations in ELF after inhalation of rIFN-gamma, we recommend inhalation rather than the parenteral route of IFN-gamma for the treatment of respiratory diseases.
Halme
M
M
Department of Pulmonary Medicine, Helsinki University Central Hospital, Finland.
Maasilta
P
P
Repo
H
H
Leirisalo-Repo
M
M
Taskinen
E
E
Mattson
K
K
Cantell
K
K
D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy; D018288:Carcinoma, Small Cell / Q000628:therapy; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008163:Luminescent Measurements; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D016676:Macrophages, Alveolar / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D007371:Interferon-gamma