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Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data.

ABSTRACT: Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration-response data. In the present study, the potential of this approach to predict the dose-dependent increase of uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration-response data of 17?-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose-response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. To evaluate the predictions made, benchmark dose (BMD) analysis was performed on the predicted dose-response data and the obtained BMDL10 values were compared with BMDL10 values derived from data on the effects of E2 and BPA in the uterotrophic assay reported in the literature. The results show that predicted dose-response data of E2 and BPA matched with the data from in vivo studies when predictions were made based on YES assay data. The YES assay-based predictions of the BMDL10 values differed 3.9-fold (E2) and 4.7- to 13.4-fold (BPA) from the BMDL10 values obtained from the in vivo data. The present study provides the proof-of-principle that PBK modelling-based reverse dosimetry of YES assay data using a minimum PBK model can predict dose-dependent in vivo uterus growth caused by estrogenic chemicals. In future studies, the approach should be extended to include other estrogens.

SUBMITTER: Zhang M

PROVIDER: S-EPMC5866837 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data.

Zhang Mengying M van Ravenzwaay Bennard B Fabian Eric E Rietjens Ivonne M C M IMCM Louisse Jochem J

Archives of toxicology 20171212 3

Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration-response data. In the present study, the potential of this approach to predict the dose-dependent increase of uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration-response data of 17β-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALU ...[more]

PMID: 29234833

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Project description:ObjectiveThe objective of this study was to develop a physiologically based pharmacokinetic model for meropenem using a retrograde approach, which could serve as a basis for prediction of the systemic and infection-site drug exposures in different populations and indications. We intended this model to be a useful tool to inform (local) pharmacokinetic-based optimal dosing of meropenem in different settings.MethodsWe developed a reduced physiologically based pharmacokinetic model with NONMEM software using a top-down approach. We used historical (previously published) data for model development and qualification. We used steady-state systemic and infection-site concentrations from 60 adult patients diagnosed with severe lung infection for model development and internal evaluation. The data included rich plasma and sparse epithelial lining fluid samples. We based the internal validation of the model on successful numerical convergence, adequate precision in parameter estimation, acceptable goodness-of-fit plot with no indication of bias, and acceptable performance of visual predictive checks. We performed external validation by fitting the model to independent data from five previously published studies: four studies in patients with pneumonia, with different grades of renal impairment, and one study in morbidly obese patients.ResultsWe successfully fitted a reduced physiologically based pharmacokinetic model with six compartments (arterial and venous pools, infection site [lungs], liver, kidneys and rest of the body) to the data and adequately estimated model parameters. We successfully qualified the model (internally and externally) using established methods. Estimated values for tissue-to-plasma partition coefficients were 0.2629 and 0.1946 for lungs and non-fat tissues (kidneys and liver), respectively. Estimated total clearance was 8.174 L/h for a typical patient with a glomerular filtration rate of 65 mL/min. Consistent with the known mechanism of meropenem elimination and previously published models, renal clearance accounted for 70% of total clearance. The model had good predictive performances on data from five different sources including populations with different characteristics with regard to body size, renal function and morbidity.ConclusionsWe successfully developed a physiologically based pharmacokinetic model for meropenem in adult patients to be used as a basis for prediction of concentrations in different groups of patients, and eventually for effective dose individualisation in different subgroups of the population.

Dataset Information

Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data.

Publications

Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data.

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