PT  - JOURNAL ARTICLE
AU  - Anson K. Abraham
AU  - Leonid Kagan
AU  - Sarmishtha Kumar
AU  - Donald E. Mager
TI  - Type I Interferon Receptor is a Primary Regulator of Target-Mediated Drug Disposition of Interferon-β in Mice
AID  - 10.1124/jpet.110.167650
DP  - 2010 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 327--332
VI  - 334
IP  - 1
4099  - http://jpet.aspetjournals.org/content/334/1/327.short
4100  - http://jpet.aspetjournals.org/content/334/1/327.full
SO  - J Pharmacol Exp Ther2010 Jul 01; 334
AB  - The purpose of this study is to evaluate the primary mechanism through which interferon (IFN)-β exhibits target-mediated drug disposition (TMDD) and whether the theoretical assumptions of TMDD models are consistent with experimental pharmacokinetic (PK) data. Recombinant murine IFN-β 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-α/β 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-β 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 μg/kg) in WT and KO animals. The concentration-time profiles for IFN-β 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-β exposure. An integrated PK/PD model was successfully used to assess the receptor-mediated disposition and dynamics of IFN-β. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics