Effect of prolonged administration of interferon-alpha on pharmacokinetics, fever, lymphocyte proliferative response, and NK cell activity.

Over a 60-week period, a patient with multiple warts received a total of 281 x 10(6) units of human leukocyte interferon (IFN-alpha) by intramuscular (IM) or intralesional (IL) injections. Circulating IFN was significantly higher following IM administration than after IL administration. These pharmacokinetics did not change. The patient's body temperature was always significantly elevated after administration of IFN. However, hyporeactivity to the febrile response developed when the interval between repeated injections of IFN was less than six days. The lymphocyte count was significantly decreased within 5-7 h after administration of IFN and had returned to normal by 24 hours, whereas total WBC, platelet, and monocyte counts were not altered. There was a depression of specific lymphocyte proliferative response to herpes simplex virus after multiple daily injections, but not after prolonged therapy. Circulating natural killer (NK) levels were not elevated during the first two months of IFN therapy. After the patient had received about 100 x 10(6) units of IFN, however, the NK cell level became elevated and remained elevated upon cessation of treatment. NK activity was stimulated by in vitro incubation of peripheral mononuclear cells with 1000 units of IFN during the initial phase of treatment. A decline of in vitro stimulation of NK activity by interferon developed during two subsequent periods of treatment with mean daily doses of 2.46 and 1.07 x 10(6) units of IFN. Long-term therapy in our patient with an average of 4.7 x 10(6) units of IFN/week was well tolerated, did not irreversibly affect platelet or white cell counts or nonspecific or virus-specific cell mediated immune responses, and enhanced circulating NK levels.