title: Subcutaneous administration of recombinant glycosylated interleukin 6 in patients with cancer: pharmacokinetics, pharmacodynamics and immunomodulatory effects.
abstract: This is the first report of the serum profile of a glycosylated recombinant form of human IL-6 (rhIL-6) administered subcutaneously (1-10 microg/kg/day) in a phase I/II trial as a thrombopoietic agent in patients with advanced cancer. The pharmacodynamic effects of IL-6 were also examined. Detailed pharmacokinetic measurements were made in four patients. Peak concentrations at 5-8 h and a median t0.5 of ca. 5 h were similar to those previously reported for non-glycosylated IL-6. However, higher peak concentrations and apparent differences in effective dose levels to those previously reported with the non-glycosylated form were seen. Indications of an apparent attenuation in circulating IL-6 concentrations with continuing injections were seen in eight of 10 patients examined but anti-IL-6 antibody generation was seen in only two patients. Soluble interleukin 6 receptor concentrations generally decreased. No major changes in T cell subsets were seen but expression of CD25 and CD54 by T lymphocytes significantly increased, accompanied by marked increases in soluble CD25 (sIL-2R) and CD54 (sICAM-1). No consistent change in B cells, monocytes or NK cells were seen. No evidence for induction of TNF-alpha was found. This study demonstrates similar biological effects of glycosylated rhIL-6 to those reported for the non-glycosylated form but illustrates several apparent differences which are discussed further.
authors.affiliation: Imperial Cancer Research Fund Cancer Medicine Research Unit, St James's University Hospital, Leeds, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Banks
authors.forename: M A
authors.initials: MA
authors.lastname: Forbes
authors.forename: P M
authors.initials: PM
authors.lastname: Patel
authors.forename: M
authors.initials: M
authors.lastname: Storr
authors.forename: S
authors.initials: S
authors.lastname: Hallam
authors.forename: D
authors.initials: D
authors.lastname: Clarke
authors.forename: D
authors.initials: D
authors.lastname: Novick
authors.forename: E
authors.initials: E
authors.lastname: Ingham
authors.forename: C
authors.initials: C
authors.lastname: Bowmer
authors.forename: J
authors.initials: J
authors.lastname: Southgate
authors.forename: L K
authors.initials: LK
authors.lastname: Trejdosiewicz
authors.forename: J
authors.initials: J
authors.lastname: Illingworth
authors.forename: T J
authors.initials: TJ
authors.lastname: Perren
authors.forename: P J
authors.initials: PJ
authors.lastname: Selby
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D015703:Antigens, CD / Q000145:classification; D015415:Biomarkers; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006031:Glycosylation; D006801:Humans; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000145:classification / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D015415:Biomarkers; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha