Type I interferon receptor is a primary regulator of target-mediated drug disposition of interferon-beta in mice

Abstract

The purpose of this study is to evaluate the primary mechanism through which interferon (IFN)-beta exhibits target-mediated drug disposition (TMDD) and whether the theoretical assumptions of TMDD models are consistent with experimental pharmacokinetic (PK) data. Recombinant murine IFN-beta was administered as an intravenous injection at two dose levels (0.5 and 1 million IU/kg) to male wild-type (WT) and type-I IFN-alpha/beta receptor subunit (IFNAR-1) knockout (KO) mice (A129S7/SvEvBrd strain). Sampling was conducted at various times (n = 3/time point), and plasma was analyzed for IFN-beta concentrations using a validated enzyme-linked immunosorbent assay. The pharmacodynamic (PD) biomarker was IP-10 mRNA that was isolated from the distal femur bone and quantified using reverse transcription-polymerase chain reaction. An integrated model that includes rapid-binding TMDD and an indirect mechanism of drug action was used to characterize the PK/PD profiles. For an experimental control, PK profiles of recombinant murine erythropoietin (muEPO), another drug that exhibits TMDD, were determined after a single intravenous dose (0.5 microg/kg) in WT and KO animals. The concentration-time profiles for IFN-beta differed substantially at initial times for the WT and KO mice at the same dose levels. These differences are characteristic of ligands exhibiting receptor-mediated disposition and were well described by a rapid-binding TMDD model. No differences in muEPO PK were observed in the control study. In summary, the intact IFNAR receptor is a primary regulator of in vivo IFN-beta exposure. An integrated PK/PD model was successfully used to assess the receptor-mediated disposition and dynamics of IFN-beta.

Fig. 1.

Mechanism-based pharmacokinetic/pharmacodynamic model for IFN-β disposition and activity. Definitions of abbreviations and model equations are listed under PK/PD Model under Materials and Methods.

Fig. 2.

Concentration-time profiles for murine IFN-β administered intravenously in WT and IFNAR-1 KO mice. Symbols are concentrations from individual mice, and the lines are model-fitted profiles for the 0.5 (A) and 1 MIU/kg (B) doses. Inset panel shows model-predictions for the 1 MIU/kg dose at early time points.

Fig. 3.

Concentration-time profiles for murine erythropoietin administered intravenously in WT and IFNAR-1 KO mice. Lines are shown that connect mean concentrations at each sampling time point.

Fig. 4.

Normalized expression levels of IP-10 mRNA in WT mice treated with IFN-β relative to control. The lines are the PK/PD model-fitted profiles, and symbols (◊, 0.5 MIU/kg; ●, 1 MIU/kg) are fold change in IP-10 mRNA expression in individual mice.