A physicochemical modelling approach for estimating the stability of soluble receptor-bound tumour necrosis...

Soluble receptors (sr) can both inhibit and stimulate cytokine bioactivity. The extent to which sr stabilizes the loss of cytokine bioactivity is an important determinant of whether a sr exerts an agonist-like or antagonist-like pharmacological effect. However, the half-life of sr-bound cytokines can be difficult to determine experimentally because methods that disrupt the sr-cytokine complex can cause loss of cytokine bioactivity. The purpose of this study was to test whether a parsimonious pharmacokinetic model in which the sr stabilizes the decay of short-lived cytokines can be used to determine the half-life of tumour necrosis factor-alpha (TNF-alpha) bound to two human urine-derived sr. A mathematical model which assumes cytokine-sr equilibrium, constant total sr concentration and first-order kinetics for loss of cytokine bioactivity was used. In addition, the model assumes that the experimentally observed bioactivity is related to the free cytokine concentration. The authors fitted experimental data reported by Aderka et al. for two TNF-alpha sr [Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) J Exp Med 175:323-329] and estimated the half-life of sr-bound TNF-alpha. The parameter estimates were plausible and comparable to those obtained by other methods and, additionally, the model predicted the unexpected relationship between sr dose and cytokine-free concentration that is observed after 9 days of TNF-alpha exposure.