Receptor-mediated pharmacokinetics and pharmacodynamics of interferon-beta1a in monkeys

Abstract

A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to simultaneously characterize interferon after i.v. and s.c. dosing at various dose levels. A sequential study in monkeys (n = 18) was conducted, where single doses of 1, 3, and 10 MIU/kg of recombinant-human interferon-beta (IFN-beta) 1a were given i.v. and then s.c. Plasma concentrations of IFN-beta were determined and biphasic neopterin concentrations were used as the pharmacodynamic (PD) endpoint. Multiple dosing also was evaluated by giving 1 MIU/kg s.c. doses once daily for 7 days (n = 3). The integrated model uses target-mediated drug disposition to describe drug elimination by receptor binding and internalization, and well characterizes the observed nonlinear pharmacokinetic (PK) profiles. The s.c. doses exhibited an absorption phase (Tmax = 3 h) and incomplete bioavailability (F = 0.3-0.7). An indirect response model for stimulation of neopterin triphosphate production by activated receptor complex followed by conversion to neopterin was used to jointly model the formation and loss of neopterin with a capacity factor Smax = 23.8. Greater relative neopterin response after s.c. dosing was accounted for by prolonged receptor activation relative to the SC50 value. Repeated daily s.c. dosing produced modestly elevated IFN-beta1a concentrations and neopterin concentrations that were lower than simulated from single-dose modeling. Although several mechanisms could be involved, these phenomena were simply remodeled as down-regulation of Smax and receptors. The PK/PD model for IFN-beta1a depicts receptor binding as a key feature controlling nonlinear elimination, nonstationary kinetics, and neopterin induction in a manner consistent with known processes controlling its disposition and pharmacological effects.