title: A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans.
abstract: Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down into different, clinically-derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence.
authors.affiliation: Department of Biological Systems Engineering, Virginia Tech, Seitz Hall, RM 210, 155 Ag Quad Lane, Blacksburg, VA 24061, USA. Electronic address: saylor@vt.edu.
authors.forename: Kyle
authors.initials: K
authors.lastname: Saylor
authors.affiliation: Department of Biological Systems Engineering, Virginia Tech, Seitz Hall, RM 210, 155 Ag Quad Lane, Blacksburg, VA 24061, USA. Electronic address: chzhang2@vt.edu.
authors.forename: Chenming
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood*; D001921:Brain / Q000378:metabolism*; D003367:Cotinine / Q000276:immunology; D006801:Humans; D008954:Models, Biological; D009538:Nicotine / Q000097:blood / Q000276:immunology* / Q000493:pharmacokinetics*; D051381:Rats; D012907:Smoking / Q000378:metabolism; D014018:Tissue Distribution; D014612:Vaccines
chemical_list: D000906:Antibodies; D014612:Vaccines; D009538:Nicotine; D003367:Cotinine
keywords: Anti-nicotine antibodies; Nicotine dependence; Nicotine disposition; Nicotine vaccine; PBPK; Physiologically based pharmacokinetic model