Phase I trial of intravenous and intraperitoneal administration of granulocyte-macrophage colony-stimulating factor.

Overview

abstract

To assess the toxicity, pharmacokinetics, and local and systemic effects of the intraperitoneal (i.p.) administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) at various dosages, 13 patients with predominantly i.p. malignancies refractory to standard chemotherapy were studied. GM-CSF was administered intravenously (i.v.) for 5 consecutive days; 21 days later the same dosage of GM-CSF was administered i.p. for 5 consecutive days. Four dosage levels were studied: 1, 2, 4, and 8 micrograms/kg/day. GM-CSF was well tolerated after i.v. and i.p. administration at doses up to 8 micrograms/kg/day. A transient fall followed by an elevation of circulating white cells was observed over a 24-h period after both i.v. and i.p. GM-CSF administration (mean minimum +/- SE as % baseline): 38 +/- 8% at 30 min after i.v. administration, 21 +/- 5% at 60 min after i.p. administration; mean maximum: 220 +/- 41% at 6 h after i.v. administration, 202 +/- 39% at 12 h after i.p. administration). The magnitude and time course of these changes were very similar for the two routes despite an up to 400-fold difference in serum GM-CSF levels at the same time points. Changes in leukocyte count and differential and neutrophil function were also similar over the 3-week period after both i.v. and i.p. administration. In the only patient who had i.p. GM-CSF levels assayed, i.p. administration achieved high levels of GM-CSF in peritoneal fluid (Cmax 343 ng/ml) with maintenance of high concentrations over 24 h (C24h 128 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)