Type I interferon receptor is a primary regulator of target-mediated drug disposition of interferon-beta in mice.
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.
Abraham
Anson K
AK
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York,Amherst, New York, USA.
Kagan
Leonid
L
Kumar
Sarmishtha
S
Mager
Donald E
DE
D000818:Animals; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007370:Interferon Type I / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
D054357:Chemokine CXCL10; D007370:Interferon Type I; D011994:Recombinant Proteins; D004921:Erythropoietin; D053633:Receptor, Interferon alpha-beta
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