A PHYSIOCHEMICAL MODELING APPROACH FOR ESTIMATING THE STABILITY OF SOLUBLE RECEPTOR-BOUND TUMOR-NECROSIS-FACTOR-ALPHA

Soluble receptors (sr) can both inhibit and stimulate cytokine bioacti vity. The extent to which sr stabilizes the loss of cytokine bioactivi ty is an important determinant of whether a sr exerts an agonist-like or antagonist-like pharmacological effect, However, the half-life of s r-bsund cytokines can be difficult to determine experimentally because methods that disrupt the sr-cytokine complex can cause loss of cytoki ne bioactivity. The purpose of this study was to test whether a parsim onious pharmacokinetic model in which the sr stabilizes the decay of s hort-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 b ioactivity was used, In addition, the model assumes that the experimen tally observed bioactivity is related to the free cytokine concentrati on, The authors fitted experimental data reported by Aderka ef al, for two TNF-alpha sr [Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallac h D (1992) J Exp Med 175:323-329] and estimated the half-life of sr-bo und TNF-alpha, The parameter estimates were plausible and comparable t o those obtained by other methods and, additionally, the model predict ed the unexpected relationship between sr dose and cytokine-free conce ntration that is observed after 9 days of TNF-alpha exposure, (C) 1997 Academic Press Limited.