Pharmacokinetics of recombinant human tumor necrosis factor alpha in rhesus monkeys after intravenous administration

Recombinant human tumor necrosis factor alpha (TNF-alpha) was administered to rhesus monkeys by i.v. short-term infusions (0.5 hr) of 10, 20, 30 and 120 micrograms/kg and long-term infusions (6.5 hr) of 22, 54, 135 and 325 micrograms/kg. At high plasma levels of TNF-alpha (doses of 120 micrograms/kg of short-term infusions and greater than or equal to 54 micrograms/kg of long-term infusion) the pharmacokinetics of TNF-alpha were practically first order. A plasma T1/2 of 1.2 to 2.1 hr was calculated. However, at low plasma levels (doses of 10-30 micrograms/kg of short-term infusion and 22 micrograms/kg of long-term infusion) the elimination rate increased steadily in dependence on concentration and time. We conclude that at low concentrations of TNF-alpha the pharmacokinetics were not first order. Simultaneous long-term infusion of recombinant human TNF-beta (200 micrograms/kg) in addition to 22 micrograms/kg of TNF-alpha reduces the elimination rate of TNF-alpha, which can be concluded from the elevation of the TNF-alpha plasma levels. Furthermore, there was no time-dependent increase of the elimination rate that was detected without infusion of TNF-beta. Based on these results two different elimination mechanisms of TNF-alpha in rhesus monkeys are postulated: an unspecific, nonsaturable process as well as a specific, saturable mechanism.