Pharmacodynamics of biological response in vivo after single and multiple doses of interferon-beta.
Interferons (IFNs) induce gene regulation in vivo that may be used to identify effective doses, schedules, and potential correlates of therapeutic response. To critically examine minimum effective dose, duration of response, and cumulative effects of repetitive doses, a range of subcutaneous doses of IFN beta ser was studied in 32 healthy human volunteers. IFN-induced products of gene regulation assessed were beta 2-microglobulin, neopterin, and tryptophan in serum and 2',5'-oligoadenylate (2-5A) synthetase activity in peripheral blood mononuclear cells. Eight subjects per group received 0.09, 0.9, 9, or 45 MU of IFN beta. Responses were measured at 24, 48, and 72 h after single and multiple doses. The lowest biologically effective dose was 0.9 MU; significant (p < 0.02) increases were observed at 24 h in beta 2-microglobulin and cellular 2-5A synthetase activity. At the two higher doses, 9 and 45 MU, changes were observed at 24 h in all products (p < 0.01). A dose response (p < 0.01) over the range of 0.09-45 MU was observed for all these serum and intracellular gene products. Changes in neopterin, beta 2-microglobulin, and cellular 2-5A synthetase correlated significantly with each other. The response to a single dose of IFN beta was as great in magnitude as the response to multiple doses, suggesting an alternate-day schedule would maintain biological response.
Witt
P L
PL
Cancer Center, Medical College of Wisconsin, Milwaukee 53226-4801.
Storer
B E
BE
Bryan
G T
GT
Brown
R R
RR
Flashner
M
M
Larocca
A T
AT
Colby
C B
CB
Borden
E C
EC
D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood; D000293:Adolescent; D000328:Adult; D001798:Blood Proteins / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006403:Hematologic Tests; D006801:Humans; D007279:Injections, Subcutaneous; D016899:Interferon-beta / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D001798:Blood Proteins; D016899:Interferon-beta; D015088:2',5'-Oligoadenylate Synthetase