title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York,Amherst, New York, USA.
authors.forename: Anson K
authors.initials: AK
authors.lastname: Abraham
authors.forename: Leonid
authors.initials: L
authors.lastname: Kagan
authors.forename: Sarmishtha
authors.initials: S
authors.lastname: Kumar
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: 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
chemical_list: D054357:Chemokine CXCL10; D007370:Interferon Type I; D011994:Recombinant Proteins; D004921:Erythropoietin; D053633:Receptor, Interferon alpha-beta
references.citation: Biopharm Drug Dispos. 2004 May;25(4):149-56
references.pmid: 15108217
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Pharm Res. 1993 Jul;10(7):1093-5
references.pmid: 8378254
references.citation: Pharm Res. 1989 Mar;6(3):192-202
references.pmid: 2542919
references.citation: J Mol Biol. 2007 Feb 16;366(2):525-39
references.pmid: 17174979
references.citation: Pharm Res. 2002 Oct;19(10):1537-43
references.pmid: 12425473
references.citation: Drug Discov Today. 2007 Dec;12(23-24):1018-24
references.pmid: 18061880
references.citation: J Interferon Cytokine Res. 1999 Oct;19(10):1069-98
references.pmid: 10547147
references.citation: Clin Pharmacol Ther. 1994 Sep;56(3):248-52
references.pmid: 7924119
references.citation: Mol Cell Biol. 1995 Aug;15(8):4208-14
references.pmid: 7623815
references.citation: Clin Pharmacol Ther. 2008 Nov;84(5):548-58
references.pmid: 18784655
references.citation: Eur J Biochem. 1987 Jul 15;166(2):303-10
references.pmid: 3301338
references.citation: Pharm Res. 2005 Oct;22(10):1589-96
references.pmid: 16180117
references.citation: Pharm Res. 1993 Apr;10(4):567-72
references.pmid: 8483840
references.citation: Biochem Pharmacol. 2009 Jun 15;77(12):1757-62
references.pmid: 19428330
references.citation: J Biol Chem. 2007 Jul 13;282(28):20053-7
references.pmid: 17502368
references.citation: Anal Biochem. 1980 Feb;102(1):176-88
references.pmid: 7356152
references.citation: J Interferon Cytokine Res. 2006 Oct;26(10):699-705
references.pmid: 17032164
references.citation: AAPS J. 2007 Jun 08;9(2):E181-9
references.pmid: 17614360
references.citation: Annu Rev Biochem. 1987;56:727-77
references.pmid: 2441659
references.citation: J Interferon Cytokine Res. 1996 Oct;16(10):759-64
references.pmid: 8910759
references.citation: Nature. 2002 Apr 18;416(6882):744-9
references.pmid: 11961557
references.citation: J Pharmacol Exp Ther. 2003 Jul;306(1):262-70
references.pmid: 12660309
references.citation: J Interferon Cytokine Res. 2000 Oct;20(10):857-66
references.pmid: 11054273
references.citation: J Pharmacokinet Biopharm. 1993 Aug;21(4):457-78
references.pmid: 8133465
references.citation: Nat Rev Immunol. 2005 Sep;5(9):675-87
references.pmid: 16110316
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Proc Natl Acad Sci U S A. 1985 May;82(10):3281-5
references.pmid: 3159015
references.citation: Science. 1994 Jun 24;264(5167):1918-21
references.pmid: 8009221
references.citation: Clin Pharmacokinet. 2005;44(4):331-47
references.pmid: 15828849
references.citation: J Pharmacokinet Pharmacodyn. 2001 Dec;28(6):507-32
references.pmid: 11999290
references.citation: J Pharmacol Exp Ther. 2001 Aug;298(2):820-4
references.pmid: 11454947