Type I Interferon Receptor is a Primary Regulator of Target-Mediated Drug Disposition of Interferon-β in Mice

Abstract

The purpose of this study is to evaluate the primary mechanism through which interferon (IFN)-␤ exhibits target-mediated drug disposition (TMDD) and whether the theoretical assumptions of TMDD models are consistent with experimental pharmacokinetic (PK) data. Recombinant murine IFN-␤ 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-␣/␤ receptor subunit (IFNAR-1) knockout (KO) mice (A129S7/SvEvBrd strain). Sampling was conducted at various times (n ϭ 3/time point), and plasma was analyzed for IFN-␤ concentrations using a validated enzymelinked 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 g/kg) in WT and KO animals. The concentration-time profiles for IFN-␤ 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-␤ exposure. An integrated PK/PD model was successfully used to assess the receptor-mediated disposition and dynamics of IFN-␤.

Mathematical analysis of the pharmacokinetic–pharmacodynamic (PKPD) behaviour of monoclonal antibodies: Predicting in vivo potency

“…Mager and Jusko [7] were the first to propose a general PK model for drugs exhibiting TMDD, which has provided the basis for extensive further studies and development (see for example [8,9,10,11,5]). Experimental confirmation of TMDD model predictions was provided in a recent elegant study by Abraham et al [12], who showed marked differences in interferon (INF)-β PK in wild-type and type-1 INF α/β receptor knockout mice.…”

“…During this initial fast phase, u and v remain approximately constant while y quickly decreases to its minimum and so we can approximate this minimum by setting u = u(0) = 1 and v = v(0) = 1. Substituting these values into (12) and ignoring the higher order terms gives an approximation to the minimum value of y as…”

A New Mouse Model Reveals a Critical Role for Host Innate Immunity in Resistance to Rift Valley Fever

“…IFN-b remained below ELISA's detection levels in sera from ZH548-infected MBT/Pas and BALB/cByJ mice. This may be due to the fact that, at low concentrations, IFN-b rapidly binds to its receptor, and serum concentrations of the free IFN-b decrease rapidly (29). In addition, we tested the susceptibility of MBT/Pas mice to other viruses.…”

Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Minireview

“…Although initially generated based on the behavior observed in a number of small‐molecule compounds mentioned above, the concept of TMDD is more widely recognized and well appreciated in peptide‐ and protein‐based pharmaceuticals (ie, large‐molecule compounds) due to the high prevalence of TMDD in this type of drug. Numerous large‐molecule compounds, including interferon‐β1a, erythropoietin, thrombopoietin, M‐CSF, pegfilgastim, and various monoclonal antibodies, have been reported to exhibit nonlinear pharmacokinetics imparted by TMDD . Different from large‐molecule compounds, which usually have high‐affinity binding to their pharmacological targets with minimal nonspecific tissue binding, the saturable target binding of small‐molecule compounds is often masked by the binding to those nonspecific sites (tissue and/or plasma) whose capacity is usually larger.…”