The tolerability and pharmacology of interleukin-6 administered in combination with GM-CSF or G-CSF in the rhesus monkey

• Published in: Toxicology (Amsterdam) Vol. 101; no. 3; pp. 157 - 166
• Main Authors: Myers, Laurie A., Boyce, John T., Robison, Rodney L.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 25.08.1995
• Subjects: Acute-phase proteins; Animals; Blood - drug effects; Blood Sedimentation - drug effects; Drug Combinations; Drug Evaluation, Preclinical; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; Granulocyte Colony-Stimulating Factor - administration & dosage; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; IL-6, interleukin-6; Injections, Subcutaneous; Interleukin-6 - administration & dosage; Interleukin-6 - toxicity; Macaca mulatta; Male; Nonhuman primates; Preclinical model; Random Allocation; Serum Albumin - drug effects; GM-CSF, granulocyte-macrophage colony-stimulating factor; Acute-phase proteins; IL-6, interleukin-6; G-CSF, granulocyte colony-stimulating factor; Nonhuman primates; Preclinical model
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/0300-483X(95)03081-P

The tolerability and potential target organ toxicity of rhIL-6 administered subcutaneously (s.c.) with rhGM-CSF or rhG-CSF were investigated in healthy nonhuman primates. Fifteen Rhesus monkeys were randomized to receive one of the following five regimens: rhIL-6, rhGM-CSF, rhG-CSF, rhIL-6 and rhGM-CSF, or rhIL-6 and rhG-CSF. Each cytokine was administered s.c. once daily at 20 μg/kg/day for 30–31 days. Marked increases in blood leukocyte counts (predominantly neutrophils) were observed in the rhGM-CSF and rhG-CSF treatment groups, but only a mild trend toward increased WBCs was observed with rhIL-6 alone. Platelet counts increased 1.7- to 2.2-fold in the rhIL-6 and rhGM-CSF groups. All regimens were well tolerated. RhIL-6, alone or in combination with either CSF, had no significant toxic effects at the dosages tested. Minimal to moderate bone marrow hyperplasia was observed in all except rhIL-6-treated animals, which correlated well with peripheral blood increases in WBCs. RhIL-6-treated animals demonstrated increased fibrinogen concentrations and erythrocyte sedimentation rates, decreased serum albumin/globulin ratios, and increased serum α-2-macroglobulin concentrations. Increased synthesis of acute-phase proteins was not observed in the other groups. Combining rhIL-6 with rhGM-CSF or rhG-CSF may reduce the rhIL-6-mediated acute-phase response while maintaining the desirable hematopoietic effects of the stimulating factors.