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Pharmacodynamics of biological response in vivo after single and multiple doses of interferon-beta
P L Witt1, B E Storer, G T Bryan
1Cancer Center, Medical College of Wisconsin, Milwaukee 53226-4801.
Abstract:
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.
Insights
Interferon beta (IFN beta) gene regulation was studied in healthy volunteers. A minimum effective dose of 0.9 MU was identified, with responses correlating across multiple biomarkers.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Interferons (IFNs) are crucial for immune response and gene regulation.
- Understanding IFN dosage and scheduling is vital for therapeutic efficacy.
- Biomarkers of IFN activity can indicate therapeutic response.
Purpose of the Study:
- To determine the minimum effective dose of subcutaneous Interferon beta (IFN beta).
- To assess the duration of response and cumulative effects of repetitive IFN beta doses.
- To identify gene regulation products as potential correlates of therapeutic response.
Main Methods:
- 32 healthy volunteers received varying subcutaneous doses of IFN beta (0.09, 0.9, 9, or 45 MU).
- IFN-induced gene products (beta 2-microglobulin, neopterin, tryptophan, 2',5'-oligoadenylate synthetase activity) were measured.
- Responses were assessed at 24, 48, and 72 hours after single and multiple doses.
Main Results:
- The lowest biologically effective dose of IFN beta was 0.9 MU.
- Significant increases in beta 2-microglobulin and 2-5A synthetase were observed at 24 hours post-dose.
- A dose-response relationship was evident across all measured biomarkers (p < 0.01).
- Changes in neopterin, beta 2-microglobulin, and 2-5A synthetase correlated significantly.
- Single and multiple doses elicited comparable response magnitudes.
Conclusions:
- 0.9 MU of IFN beta is the minimum effective dose for inducing gene regulation.
- An alternate-day dosing schedule may be sufficient to maintain biological response.
- Measured gene products serve as reliable biomarkers for IFN beta activity and therapeutic response.