caa a22 4500 60553389X CHVBK 20210128100840.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10928-015-9413-5 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9413-5 The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments [Elektronische Daten] [Tarjinder Sahota, Meindert Danhof, Oscar Della Pasqua] Current toxicity protocols relate measures of systemic exposure (i.e. AUC, Cmax) as obtained by non-compartmental analysis to observed toxicity. A complicating factor in this practice is the potential bias in the estimates defining safe drug exposure. Moreover, it prevents the assessment of variability. The objective of the current investigation was therefore (a) to demonstrate the feasibility of applying nonlinear mixed effects modelling for the evaluation of toxicokinetics and (b) to assess the bias and accuracy in summary measures of systemic exposure for each method. Here, simulation scenarios were evaluated, which mimic toxicology protocols in rodents. To ensure differences in pharmacokinetic properties are accounted for, hypothetical drugs with varying disposition properties were considered. Data analysis was performed using non-compartmental methods and nonlinear mixed effects modelling. Exposure levels were expressed as area under the concentration versus time curve (AUC), peak concentrations (Cmax) and time above a predefined threshold (TAT). Results were then compared with the reference values to assess the bias and precision of parameter estimates. Higher accuracy and precision were observed for model-based estimates (i.e. AUC, Cmax and TAT), irrespective of group or treatment duration, as compared with non-compartmental analysis. Despite the focus of guidelines on establishing safety thresholds for the evaluation of new molecules in humans, current methods neglect uncertainty, lack of precision and bias in parameter estimates. The use of nonlinear mixed effects modelling for the analysis of toxicokinetics provides insight into variability and should be considered for predicting safe exposure in humans. The Author(s), 2015 Toxicokinetics nationallicence NOAEL nationallicence Safety margin nationallicence Model-based drug development nationallicence AUC : Area under the concentration versus time curve nationallicence Cmax : Peak concentrations nationallicence ICH : International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use nationallicence PD : Pharmacodynamics nationallicence PK : Pharmacokinetics nationallicence TAT : Time above a concentration threshold nationallicence Sahota Tarjinder Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands aut Danhof Meindert Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands aut Della Pasqua Oscar Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/3(2015-06-01), 251-261 1567-567X 42:3<251 2015 42 10928 https://doi.org/10.1007/s10928-015-9413-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9413-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sahota Tarjinder Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands aut NATIONALLICENCE 700 1- Danhof Meindert Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands aut NATIONALLICENCE 700 1- Della Pasqua Oscar Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/3(2015-06-01), 251-261 1567-567X 42:3<251 2015 42 10928