The dissociation of GM‐CSF efficacy from toxicity according to route of administration: a pharmacodynamic study

Jonathan Cebon, Graham John Lieschke, Ross William Bury, George Morstyn

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Abstract

Summary. The pharmacokinetics and pharmacodynamics of bacterially synthesized granulocyte‐macrophage colony stimulating factor (GM‐CSF) were studied in 33 patients. GM‐CSF (0·3–30 μg/kg/d) was administered subcutaneously (s.c.) or intravenously (i.v.) by bolus or 2 h infusion for 10 d to three patients at each dose level, and serum levels measured by enzyme‐linked immunosorbent assay (ELISA). Relationships between pharmacokinetic variables and GM‐CSF efficacy and toxicity were investigated. GM‐CSF appeared more effective s.c. than i.v. Correlations with response improved when patients with neutropenia or marrow infiltration by tumour were excluded. For the remaining patients, the correlation coefficients between the day 10 leucocyte count was highest with dose (R = 0·629, P < 0·01), the duration GM‐CSF concentrations exceeded 1 ng/ml (R = 0·524, P < 0·05) and area under the concentration‐time curve (R = 0·508, P < 0·05). There was no correlation with peak serum GM‐CSF (Cmax) (R = 0·188, P=NS). In contrast, the first dose reaction (characterized by hypoxaemia and hypotension) was associated with high Cmax (P < 0·01) and i.v. administration. Fever, liver enzyme elevation and pericarditis occurred at 10–30 μg/kg and were not influenced by route. Since the variables correlating with response differed from those correlating with these toxicities, it appears that the therapeutic index for GM‐CSF can be increased by modifying the method of administration. 1992 Blackwell Publishing Ltd

Original languageEnglish
Pages (from-to)144-150
Number of pages7
JournalBritish Journal of Haematology
Volume80
Issue number2
DOIs
Publication statusPublished - 1992
Externally publishedYes

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