Clinical pharmacology of recombinant cytokines

The explosive growth in cytokines has been followed by many attempts to bri ng them into clinical use. Immediate applications are already recognized in cancer and infectious diseases. Future applications are foreseeable in inf lammatory and auto-immune diseases. The use of accurate and sensitive metho ds 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 co nvenient method but there is an urgent need for a real standardization of t his technique. Moreover, ELISA may be susceptible to cross-reactivity due t o the high percentage of amino-acid homolog between the various cytokines. The pharmacokinetic profil of recombinant cytokines may be influenced by en dogenous production, receptor binding effect, receptor antagonists and solu ble receptors. Cytokines elicit an immunogenic response and anticytokine an tibodies should be monitored. Serum half-life of elimination is about 4 h a fter subcutaneous administration. In contrast with conventional drugs, phar macokinetic data do not provide useful information for the design of a clin ical protocol, and the rational choice of the unit dose and dosing schedule should be based on biological considerations. In vitro studies on the dura tion of receptor occupancy required for effector augmentation provide one o f the bases for the choice of therapeutic protocol. Recombinant cytokines share biological activities and synergize with or ant agonize one another so that it is difficult to evaluate their effects in cl inical studies. Thus, pharmacological results do not always correlate with therapeutic effect. There is no direct relationship between dose and activi ty. One must determine the optimum biological dose (OBD), which is the mini mal dose resulting in a significant augmentation of effector cell activity correlating with the therapeutic response. Surrogate markers may help to as sess the clinical response such as 2',5'-oligo(A) synthetase or neopterin f ollowing interferon administration. Cytokines' adverse effects are difficult to foresee in the human because st udies in rodents and dogs cannot fully predict them because of their specie s specificity. New relevant animal models are needed such as transgenic ani mals and parallel animal models. Proinflammatory cytokines inhibit cytochro me P450 and have the potential to cause drug-cytokine interactions.