Widera, Agata

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EXCLI Journal 2015;14:1014-1016 – ISSN 1611-2156 Received: August 26, 2015, accepted: August 31, 2015, published: September 01, 2015   1014 Guest editorial: HIGHLIGHT REPORT: INTERSPECIES EXTRAPOLATION BY PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING  Dr. Agata Widera  Leibniz Research Centre for Working Environment and Human Factors, IfADo - Ardeystr. 67, D-44139 Dortmund – Germany; Phone: ++49(0)2311084 256; Fax: ++49(0)2311084 403;  E-mail address: Widera@ifado.de   http://dx.doi.org/10.17179/excli2015-548  This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).    Recently, several articles have been pub-lished questioning the usefulness of animal experiments for prediction of human toxicity (Leist and Hartung, 2013). For example, it has been reported that there is almost no cor-relation of gene expression alterations in-duced by inflammatory stimuli in humans and mice (Seok et al., 2013). However, a re-cent study of Thiel et al. (2015) demonstrates that this view may be too pessimistic. Based on pharmacokinetic modeling, Thiel et al. (2015) demonstrated a surprisingly precise mouse to human extrapolation for 10 exem-plary pharmaceuticals. For interspecies mod-eling the authors adjusted four parameter domains in PBPK models: (i) Species-specific physiology, including more than 500 individual parameters, for example organ size and blood flow; (ii) the fraction of non-protein bound test compound; (iii) pharma-cokinetic parameters, such as Km and Vmax for the predominant route of clearance, (iv) tissue specific gene expression of the most important genes responsible for elimination of the test compound (Thiel et al., 2015). Adjusting these parameter domains leads to a very good fit of mouse to human extrapolat-ed plasma concentrations of the test com-pounds compared to measured human plas-ma concentrations. One of the limitations of the study of Thiel et al. (2015) is the use of gene expression data for simulation of the influence of metabolizing enzymes and car-riers involved in clearance of the test com-pounds. Since the activities and not RNA levels are relevant in this context, the RNA based approximation can certainly be further improved. However, establishment of a tis-sue and species specific directory of all rele-vant metabolizing activities still represents an important future project.  Currently, much effort is invested in re-search on in vitro systems (Frey et al., 2014; Kim et al., 2015; Hammad and Ahmed, 2014), particularly in the fields of hepatotox-icity (Godoy et al., 2013; Grinberg et al., 2014; Ghallab, 2014; Schug et al., 2013), neurotoxicity (Balmer et al., 2014; Wald-mann et al., 2014; Krug et al., 2013; Stöber, 2014) and nephrotoxicity (Giustarini et al., 2009; Faiz et al., 2011). These studies de-pend on knowledge of in vivo relevant con-centrations which should be covered by in vitro testing. A precise extrapolation of dos-es in vivo to blood concentrations or even better compound concentrations at the target cells of toxicity is therefore critical for pro-gress in the field of alternative methods and can best be achieved by systematic PBPK modeling (Mielke et al., 2011; Sterner et al., EXCLI Journal 2015;14:1014-1016 – ISSN 1611-2156 Received: August 26, 2015, accepted: August 31, 2015, published: September 01, 2015   1015 2013; Strikwold et al., 2013; Wang et al., 2000). Further progress may be achieved by combining PBPK models with the recently established spatio-temporal models (Hoehme et al., 2010; Drasdo et al., 2014a) which can simulate metabolism at the level of individu-al cells (Schliess et al., 2014; Drasdo et al., 2014b; Widera, 2014). The here discussed study of Thiel and colleagues improves the reliability of extrapolating compound con-centrations from mice to human by the sys-tematic adaptation of species specific model parameters and therefore is of high relevance not only for the planning of first-in-man studies but also for an improved use of in vitro systems for prediction of human toxici-ty.   REFERENCES Balmer NV, Klima S, Rempel E, Ivanova VN, Kolde R, Weng MK, et al. From transient transcriptome re-sponses to disturbed neurodevelopment: role of his-tone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014;88:1451-68.  Drasdo D, Bode J, Dahmen U, Dirsch O, Dooley S, Gebhardt R, et al.The virtual liver: state of the art and future perspectives. Arch Toxicol. 2014a;88:2071-5.  Drasdo D, Hoehme S, Hengstler JG. How predictive quantitative modelling of tissue organisation can in-form liver disease pathogenesis. J Hepatol. 2014b;61: 951-6.  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Highlight report: Interspecies extrapolation by physiologically based pharmacokinetic modeling

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Highlight report: Interspecies extrapolation by physiologically based pharmacokinetic modeling

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