title: A phase I trial of recombinant human interferon-gamma in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS).
abstract: A Phase I study of recombinant interferon-gamma (rIFN-gamma) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-gamma. rIFN-gamma was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2-4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7-12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1-1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-gamma is given at doses at or near this MTD.
authors.affiliation: Laboratory of Immunoregulation, NIAID, Bethesda, Maryland 20892.
authors.forename: H C
authors.initials: HC
authors.lastname: Lane
authors.forename: R T
authors.initials: RT
authors.lastname: Davey
authors.forename: S A
authors.initials: SA
authors.lastname: Sherwin
authors.forename: H
authors.initials: H
authors.lastname: Masur
authors.forename: A H
authors.initials: AH
authors.lastname: Rook
authors.forename: J F
authors.initials: JF
authors.lastname: Manischewitz
authors.forename: G V
authors.initials: GV
authors.lastname: Quinnan
authors.forename: P D
authors.initials: PD
authors.lastname: Smith
authors.forename: M E
authors.initials: ME
authors.lastname: Easter
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000276:Adjuvants, Immunologic; D000293:Adolescent; D000328:Adult; D003587:Cytomegalovirus / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004341:Drug Evaluation / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012514:Sarcoma, Kaposi / Q000188:drug therapy*
chemical_list: D000276:Adjuvants, Immunologic; D011994:Recombinant Proteins; D007371:Interferon-gamma