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Development and Evaluation of an In Silico Dermal Absorption Model Relevant for Children.

ABSTRACT: The higher skin surface area to body weight ratio in children and the prematurity of skin in neonates may lead to higher chemical exposure as compared to adults. The objectives of this study were: (i) to provide a comprehensive review of the age-dependent anatomical and physiological changes in pediatric skin, and (ii) to construct and evaluate an age-dependent pediatric dermal absorption model. A comprehensive review was conducted to gather data quantifying the differences in the anatomy and physiology of child and adult skin. Maturation functions were developed for model parameters that were found to be age-dependent. A pediatric dermal absorption model was constructed by updating a MoBi implementation of the Dancik et al. 2013 skin permeation model with these maturation functions. Using a workflow for adult-to-child model extrapolation, the predictive performance of the model was evaluated by comparing its predicted rates of flux of diamorphine, phenobarbital and buprenorphine against experimental observations using neonatal skin. For diamorphine and phenobarbital, the model provided reasonable predictions. The ratios of predicted:observed flux in neonates for diamorphine ranged from 0.55 to 1.40. For phenobarbital, the ratios ranged from 0.93 to 1.26. For buprenorphine, the model showed acceptable predictive performance. Overall, the physiologically based pediatric dermal absorption model demonstrated satisfactory prediction accuracy. The prediction of dermal absorption in neonates using a model-based approach will be useful for both drug development and human health risk assessment.

SUBMITTER: Yun YE

PROVIDER: S-EPMC8780349 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This guidance on the assessment of dermal absorption has been developed to assist notifiers, users of test facilities and Member State authorities on critical aspects related to the setting of dermal absorption values to be used in risk assessments of active substances in Plant Protection Products (PPPs). It is based on the 'scientific opinion on the science behind the revision of the guidance document on dermal absorption' issued in 2011 by the EFSA Panel on Plant Protection Products and their Residues (PPR). The guidance refers to the EFSA PPR opinion in many instances. In addition, the first version of this guidance, issued in 2012 by the EFSA PPR Panel, has been revised in 2017 on the basis of new available data on human in vitro dermal absorption for PPPs and wherever clarifications were needed. Basic details of experimental design, available in the respective test guidelines and accompanying guidance for the conduct of studies, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with PPPs are given. Issues discussed include a brief description of the skin and its properties affecting dermal absorption. To facilitate use of the guidance, flow charts are included. Guidance is also provided, for example, when there are no data on dermal absorption for the product under evaluation. Elements for a tiered approach are presented including use of default values, data on closely related products, in vitro studies with human skin (regarded to provide the best estimate), data from experimental animals (rats) in vitro and in vivo, and the so called 'triple pack' approach. Various elements of study design and reporting that reduce experimental variation and aid consistent interpretation are presented. A proposal for reporting data for assessment reports is also provided. The issue of nanoparticles in PPPs is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of PPPs.

Project description:BackgroundAn agent-based modeling approach has been suggested as an alternative to traditional, equation-based modeling methods for describing oral drug absorption. It enables researchers to gain a better understanding of the pharmacokinetic (PK) mechanisms of a drug. This project demonstrates that a biomimetic agent-based model can adequately describe the absorption and disposition kinetics both of midazolam and clonazepam.MethodsAn agent-based biomimetic model, in silico drug absorption tract (ISDAT), was built to mimic oral drug absorption in humans. The model consisted of distinct spaces, membranes, and metabolic enzymes, and it was altogether representative of human physiology relating to oral drug absorption. Simulated experiments were run with the model, and the results were compared to the referent data from clinical equivalence trials. Acceptable similarity was verified by pre-specified criteria, which included 1) qualitative visual matching between the clinical and simulated concentration-time profiles, 2) quantitative similarity indices, namely, weighted root mean squared error (RMSE), and weighted mean absolute percentage error (MAPE) and 3) descriptive similarity which requires less than 25% difference between key PK parameters calculated by the clinical and the simulated concentration-time profiles. The model and its parameters were iteratively refined until all similarity criteria were met. Furthermore, simulated PK experiments were conducted to predict bioavailability (F). For better visualization, a graphical user interface for the model was developed and a video is available in Supporting Information.ResultsSimulation results satisfied all three levels of similarity criteria for both drugs. The weighted RMSE was 0.51 and 0.92, and the weighted MAPE was 5.99% and 8.43% for midazolam and clonazepam, respectively. Calculated PK parameter values, including area under the curve (AUC), peak plasma drug concentration (Cmax), time to reach Cmax (Tmax), terminal elimination rate constant (Kel), terminal elimination half life (T1/2), apparent oral clearance (CL/F), and apparent volume of distribution (V/F), were reasonable compared to the referent values. The predicted absolute oral bioavailability (F) was 44% for midazolam (literature reported value, 31-72%) and 93% (literature reported value, ≥ 90%) for clonazepam.ConclusionThe ISDAT met all the pre-specified similarity criteria for both midazolam and clonazepam, and demonstrated its ability to describe absorption kinetics of both drugs. Therefore, the validated ISDAT can be a promising platform for further research into the use of similar in silico models for drug absorption kinetics.

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Development and Evaluation of an In Silico Dermal Absorption Model Relevant for Children.

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