Extrapolation of experimental safety data to humans: The interleukin-6 case

Interleukin 6 (IL-6) has a broad spectrum of biological activities, which include stimulation of hemopoiesis, especially thrombopoiesis, of the immune response, proliferation of mesangium cells, and induction of acute-phase proteins in the liver. Therefore, the therapeutic use of IL-6 for any specific clinical indication, e.g., stimulation of thrombopoiesis in severe thrombocytopenia, may be complicated by nonspecific effects. Preclinical experimental investigations of the safety evaluation performed in primates and rodents showed that rhIL-6 is well tolerated. A two- to three-fold increase in thrombocyte counts was observed along with an increase in acute-phase proteins and immunostimulation in the absence of target organ toxicity. Patients receiving rhIL-6, however, had a vigorous acute-phase response, with fever, anemia, and general malaise. Importantly, rhIL-6 administration did not cause mesangioproliferative nephritis or an uncontrolled lymphoproliferation as predicted from IL-6 transgenic mice. Although preclinical investigations are in general quite predictive for humans, safety data should be extrapolated carefully, since important quantitative differences may occur. (C) 1997 Academic Press.