The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments
| LEADER | caa a22 4500 | ||
|---|---|---|---|
| 001 | 60553389X | ||
| 003 | CHVBK | ||
| 005 | 20210128100840.0 | ||
| 007 | cr unu---uuuuu | ||
| 008 | 210128e20150601xx s 000 0 eng | ||
| 024 | 7 | 0 | |a 10.1007/s10928-015-9413-5 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-015-9413-5 | ||
| 245 | 0 | 4 | |a The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments |h [Elektronische Daten] |c [Tarjinder Sahota, Meindert Danhof, Oscar Della Pasqua] |
| 520 | 3 | |a 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. | |
| 540 | |a The Author(s), 2015 | ||
| 690 | 7 | |a Toxicokinetics |2 nationallicence | |
| 690 | 7 | |a NOAEL |2 nationallicence | |
| 690 | 7 | |a Safety margin |2 nationallicence | |
| 690 | 7 | |a Model-based drug development |2 nationallicence | |
| 690 | 7 | |a AUC : Area under the concentration versus time curve |2 nationallicence | |
| 690 | 7 | |a Cmax : Peak concentrations |2 nationallicence | |
| 690 | 7 | |a ICH : International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use |2 nationallicence | |
| 690 | 7 | |a PD : Pharmacodynamics |2 nationallicence | |
| 690 | 7 | |a PK : Pharmacokinetics |2 nationallicence | |
| 690 | 7 | |a TAT : Time above a concentration threshold |2 nationallicence | |
| 700 | 1 | |a Sahota |D Tarjinder |u Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands |4 aut | |
| 700 | 1 | |a Danhof |D Meindert |u Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands |4 aut | |
| 700 | 1 | |a Della Pasqua |D Oscar |u Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/3(2015-06-01), 251-261 |x 1567-567X |q 42:3<251 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-015-9413-5 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s10928-015-9413-5 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Sahota |D Tarjinder |u Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Danhof |D Meindert |u Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Della Pasqua |D Oscar |u Division of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, The Netherlands |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/3(2015-06-01), 251-261 |x 1567-567X |q 42:3<251 |1 2015 |2 42 |o 10928 | ||