Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-beta 1a in humans.

Abstract

An integrated receptor-based pharmacokinetic/pharmacodynamic (PK/PD) model of interferon-beta la (IFN-beta la) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans. Data were extracted from the literature by digitalization. Single-dose (3 IV doses and I SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program. Additional submodels incorporating neutralizing antibody formation and negative feedback inhibition were applied to account for drug accumulation and lower than expected neopterin concentrations encountered after multiple-dosing (1 SC dose every 48 hs). The basic model jointly-captured the nonlinear PK behavior of the drug and induced neopterin concentrations after all single doses. Slow and incomplete absorption (F = 0.33) of the SC dose resulted in prolonged drug concentrations reflective of flip-flop kinetics. Despite lower drug concentrations, SC dosing produced a similar neopterin profile as compared with the IV doses; however, with a longer time to peak effect and slightly higher neopterin concentrations at later time points. The PD component of the model represents a modified precursor-dependent indirect response model driven by the amount of internalized drug-receptor complex. The latter stimulated a 6-fold increase in the production of the neopterin precursor (Smax = 5.89). Drug accumulation and lower than expected neopterin concentrations after multiple dosing were also captured after the inclusion of the submodels. The present integrated PK/PD model for IFN-beta 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.