[Pharmacology of recombinant cytokines]

The explosive growth in cytokines has been followed by many attempts to bring them into clinical use. Immediate applications are already recognized in cancer and infectious diseases. Future applications are foreseeable in inflammatory and auto-immune diseases. The use of accurate and sensitive methods for cytokine measurements in body fluids is an absolute prerequisite to define the pharmacological effect of parenterally administered recombinant cytokines. Enzyme-linked immunosorbent assay (ELISA) has become the most convenient method but there is an urgent need for a real standardization of this technique. Moreover, ELISA may be susceptible to cross-reactivity due to the high percentage of amino-acid homology between the various cytokines. The pharmacokinetic profile of recombinant cytokines may be influenced by endogenous production, receptor binding effect, receptor antagonists and soluble receptors. Cytokines elicit an immunogenic response and anticytokine antibodies should be monitored. Serum half-life of elimination is about 4 h after subcutaneous administration. In contrast with conventional drugs, pharmacokinetic data do not provide useful information for the design of a clinical protocol, and the rational choice of the unit dose and dosing schedule should be based on biological considerations. In vitro studies on the duration of receptor occupancy required for effector augmentation provide one of the bases for the choice of therapeutic protocol. Recombinant cytokines share biological activities and synergize with or antagonize one another so that it is difficult to evaluate their effects in clinical studies. Thus, pharmacological results do not always correlate with therapeutic effect. There is no direct relationship between dose and activity. One must determine the optimum biological dose (OBD), which is the minimal dose resulting in a significant augmentation of effector cell activity correlating with the therapeutic response. Surrogate markers may help to assess the clinical response such as 2',5'-oligo(A) synthetase or neopterin following interferon administration. Cytokines' adverse effects are difficult to foresee in the human because studies in rodents and dogs cannot fully predict them because of their species specificity. New relevant animal models are needed such as transgenic animals and parallel animal models. Pro-inflammatory cytokines inhibit cytochrome P-450 and have the potential to cause drug-cytokine interactions.