A Systematic Evaluation of the Use of Physiologically Based Pharmacokinetic Modeling for Cross-Species Extrapolation

Thiel, Christoph; Schneckener, Sebastian; Krauß, Markus; Ghallab, Ahmed; Hofmann, Ute; Kanacher, Tobias; Zellmer, Sebastian; Gebhardt, Rolf; Hengstler, Jan G.; Kuepfer, Lars

doi:10.1002/jps.24214

Cited by 99 publications

(98 citation statements)

References 82 publications

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“…Recently, it was shown that species-specific physiology has the highest influence on the predictive quality of PBPK-based cross-species extrapolation (Thiel et al 2015). The rat PBPK model of azathioprine (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4). This mechanistic translation was based on recent findings (Thiel et al 2015) and helped to compensate the unavailability of adequate PK data for the rat in the literature. Gene expression data of azathioprine-treated rats (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, the quality of the developed PBPK model of azathioprine was assessed by comparing simulated PK data with different experimental concentration–time profiles from the literature (Odlind et al 1986; Van Os et al 1996; Zins et al 1997). To indicate the model quality, PBPK models were evaluated by calculating a root-mean-square deviation (RMSD) whereby the differences of measured and simulated concentrations were normalized by respective experimental values (Thiel et al 2015). Moreover, a linear regression was performed for simulated and observed concentrations.…”

Section: Methodsmentioning

confidence: 99%

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Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

et al. 2016

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Understanding central mechanisms underlying drug-induced toxicity plays a crucial role in drug development and drug safety. However, a translation of cellular in vitro findings to an actual in vivo context remains challenging. Here, physiologically based pharmacokinetic (PBPK) modeling was used for in vivo contextualization of in vitro toxicity data (PICD) to quantitatively predict in vivo drug response over time by integrating multiple levels of biological organization. Explicitly, in vitro toxicity data at the cellular level were integrated into whole-body PBPK models at the organism level by coupling in vitro drug exposure with in vivo drug concentration–time profiles simulated in the extracellular environment within the organ. PICD was exemplarily applied on the hepatotoxicant azathioprine to quantitatively predict in vivo drug response of perturbed biological pathways and cellular processes in rats and humans. The predictive accuracy of PICD was assessed by comparing in vivo drug response predicted for rats with observed in vivo measurements. To demonstrate clinical applicability of PICD, in vivo drug responses of a critical toxicity-related pathway were predicted for eight patients following acute azathioprine overdoses. Moreover, acute liver failure after multiple dosing of azathioprine was investigated in a patient case study by use of own clinical data. Simulated pharmacokinetic profiles were therefore related to in vivo drug response predicted for genes associated with observed clinical symptoms and to clinical biomarkers measured in vivo. PICD provides a generic platform to investigate drug-induced toxicity at a patient level and thus may facilitate individualized risk assessment during drug development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1723-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

et al. 2016

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“…In this study we collect available pharmacokinetic data on cephalosporins of a range of food-producing (cattle, pigs, chickens, rabbits, horses) and companion animal (dogs, cats, rabbits, horses) species and assess the accuracy of interspecies extrapolation by allometric scaling of pharmacokinetic data over this broad range of animal species. We have opted for allometric scaling because this technique is less time consuming and requires less input parameters than more refined methods for interspecies extrapolation, like physiologically based pharmacokinetic (PBPK) modelling [12–14]. Also, allometric scaling is a more widely applied and understood technique.…”

Section: Introductionmentioning

confidence: 99%

Modelling concentrations of antimicrobial drugs: comparative pharmacokinetics of cephalosporin antimicrobials and accuracy of allometric scaling in food-producing and companion animals

et al. 2016

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BackgroundTo optimize antimicrobial dosing in different animal species, pharmacokinetic information is necessary. Due to the plethora of cephalosporin antimicrobials and animal species in which they are used, assessment of pharmacokinetics in all species is unfeasible. In this study we aimed to describe pharmacokinetic data of cephalosporins by reviewing the available literature for food producing and companion animal species. We assessed the accuracy of interspecies extrapolation using allometric scaling techniques to determine pharmacokinetic characteristics of cephalosporins in animal species for which literature data is unavailable. We assessed the accuracy of allometric scaling by comparing the predicted and the published pharmacokinetic value in an animal species/humans not included in the allometric modelling.ResultsIn general, excretion of cephalosporins takes place mainly through renal mechanisms in the unchanged form and volume of distribution is limited in all animal species. Differences in plasma protein binding capacity and elimination half-life are observed but available information was limited. Using allometric scaling, correlations between body weight (BW) and volume of distribution (Vd) and clearance (Cl) were R 2 > 0.97 and R 2 > 0.95 respectively for ceftazidime, ceftiofur, cefquinome and cefepime but not ceftriaxone. The allometric exponent ranged from 0.80 to 1.31 for Vd and 0.83 to 1.24 for Cl. Correlations on half-life ranged from R2 0.07–0.655 (literature) and R2 0.102–0.876 (calculated).ConclusionsAllometric scaling can be applied for interspecies extrapolation of cephalosporin pharmacokinetic parameters Vd and Cl, but not elimination half-life. We hypothesize that the accuracy could be improved by using more refined scaling techniques.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0817-2) contains supplementary material, which is available to authorized users.

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“…In recent years, much progress has been achieved in PBPK modeling Thiel et al 2015;Jones et al 2009;Meyer et al 2012). Moreover, techniques of spatio-temporal tissue modeling have been established that allow simulations of how specific biological processes contribute to liver function (Hoehme et al 2017;Friebel et al 2015;Drasdo et al 2014a, b;Schliess et al 2014;Vartak et al 2016).…”

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confidence: 99%

Highlight report: physiologically-based modeling of diseased liver tissue

Bolt

2017

Arch Toxicol

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A Systematic Evaluation of the Use of Physiologically Based Pharmacokinetic Modeling for Cross-Species Extrapolation

Cited by 99 publications

References 82 publications

Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

Modelling concentrations of antimicrobial drugs: comparative pharmacokinetics of cephalosporin antimicrobials and accuracy of allometric scaling in food-producing and companion animals

Highlight report: physiologically-based modeling of diseased liver tissue

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