PBK modelling of topical application and characterisation of the uncertainty of Cmax estimate: A case study approach.
Toxicol Appl Pharmacol
; 442: 115992, 2022 05 01.
Article
em En
| MEDLINE
| ID: mdl-35346730
ABSTRACT
Combined with in vitro bioactivity data, physiologically based kinetic (PBK) models has increasing applications in next generation risk assessment for animal-free safety decision making. A tiered framework of building PBK models for such application has been developed with increasing complexity and refinements, as model parameters determined in silico, in vitro, and with human pharmacokinetic data become progressively available. PBK modelling has been widely applied for oral/intravenous administration, but less so on topically applied chemicals. Therefore, building PBK models for topical applications and characterizing their uncertainties in the tiered approach is critical to safety decision making. The purpose of this study was to assess the confidence of PBK modelling of topically applied chemicals following the tiered framework, using non-animal methods derived parameters. Prediction of maximum plasma concentration (Cmax) and area under the curve were compared to observed kinetics from published dermal clinical studies for five chemicals (diclofenac, salicylic acid, coumarin, nicotine, caffeine). A bespoke Bayesian statistical model was developed to describe the distributions of Cmax errors between the predicted and observed data. We showed a general trend that confidence in model predictions increases when more quality in vitro data, particularly those on hepatic clearance and dermal absorption, are available as model input. The overall fold error distributions are useful for characterizing model uncertainty. We concluded that by identifying and quantifying the uncertainties in the tiered approach, we can increase the confidence in using PBK modelling to help make safety decisions on topically applied chemicals in the absence of human pharmacokinetic data.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fígado
/
Modelos Biológicos
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article