title: Pharmacokinetic-pharmacodynamic modeling of alpha interferon response induced by a Toll-like 7 receptor agonist in mice.
abstract: Recombinant alpha interferon (IFN-alpha) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-alpha and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-alpha as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Ramsgate Road, Sandwich, United Kingdom. neil.benson@pfizer.com
authors.forename: Neil
authors.initials: N
authors.lastname: Benson
authors.forename: Joost
authors.initials: J
authors.lastname: de Jongh
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Duckworth
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Henry E
authors.initials: HE
authors.lastname: Pertinez
authors.forename: Jaiessh K
authors.initials: JK
authors.lastname: Rawal
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: van Steeg
authors.forename: Piet H
authors.initials: PH
authors.lastname: Van der Graaf
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000493:pharmacokinetics; D000818:Animals; D021461:Animals, Outbred Strains; D000998:Antiviral Agents / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000276:immunology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; C508876:SM360320; D051199:Toll-Like Receptor 7; D000225:Adenine