• 약학회지
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• 제59권1호
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• pp.29-39
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• 2015

In recent years, physiologically based pharmacokinetic (PBPK) modeling has been widely used in pharmaceutical industries as well as regulatory health authorities for drug discovery and development. Several application areas of PBPK have been introduced so far including drug-drug interaction prediction, transporter-mediated interaction prediction, and pediatric PK prediction. The purpose of this review is to introduce PBPK and illustrates one of its application areas, particularly pediatric PK prediction by utilizing existing adult PK data and in vitro data. The evaluation of the initial PBPK for adult was done by comparing with experimental PK profiles and the scaling from adult to pediatric was conducted using age-related changes in size such as tissue compartments, and protein binding etc. Sotalol and lorazepam were selected in this review as model drugs for this purpose and were re-evaluated using the PBPK models by GastroPlus$^{(R)}$. The challenges and strategies of PBPK models using adult PK data as well as appropriate in vitro assay data for extrapolating pediatric PK at various ages were also discussed in this paper.

• 한국임상약학회지
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• 제31권2호
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• pp.125-135
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• 2021

Background: Generally, pharmacokinetics (PK) models could be stratified into two models. The compartment PK model uses the concept of simple compartmentalization to describe complex bodies, and the physiologically based pharmacokinetic (PBPK) model describes the body using multi-compartment networking. Notwithstanding sharing a theoretical background in both models, there was still a lack of knowledge to enhance compatibility in both models. Objective: This study aimed to evaluate the compatibility among PBPK, lumping model and compartment PK model with voriconazole PK case study. Methods: The number of compartments and blood flow on each tissue in the PBPK model were modified using the lumping method, considering physiological similarities. The concentration-time profiles and area under the concentration-time curve (AUC) parameters were simulated at each model, assuming taken voriconazole oral 400 mg single dose. After that, those mentioned PK parameters were compared. Results: The PK profiles and parameters of voriconazole in the three models were similar that proves their compatibility. The AUC of central compartment in the PBPK and lumping model was within a 2-fold range compared to those in the 2- compartment model. The AUC of non-eliminating tissues compartment in the PBPK model was similar to those in the lumping model. Conclusion: Regarding the compatibility of the three PK models, the utilization of the lumping method was confirmed by suggesting its reliable PK parameters with PBPK and compartment PK models. Further case studies are recommended to confirm our findings.

• 대한예방의학회:학술대회논문집
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• 대한예방의학회 2004년도 제56차 추계 학술대회 연제집
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• pp.60.2-61
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• 2004

• Toxicological Research
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• 제32권1호
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• pp.15-20
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• 2016

Physiologically based pharmacokinetic (PBPK) modeling can provide an effective way to utilize in vitro and in silico based information in modern risk assessment for children and other potentially sensitive populations. In this review, we describe the process of in vitro to in vivo extrapolation (IVIVE) to develop PBPK models for a chemical in different ages in order to predict the target tissue exposure at the age of concern in humans. We present our on-going studies on pyrethroids as a proof of concept to guide the readers through the IVIVE steps using the metabolism data collected either from age-specific liver donors or expressed enzymes in conjunction with enzyme ontogeny information to provide age-appropriate metabolism parameters in the PBPK model in the rat and human, respectively. The approach we present here is readily applicable to not just to other pyrethroids, but also to other environmental chemicals and drugs. Establishment of an in vitro and in silico-based evaluation strategy in conjunction with relevant exposure information in humans is of great importance in risk assessment for potentially vulnerable populations like early ages where the necessary information for decision making is limited.

• Toxicological Research
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• 제35권4호
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• pp.295-301
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• 2019

In this review, we describe the absorption rates (Caco-2 cell permeability) and hepatic/plasma pharmacokinetics of 53 diverse chemicals estimated by modeling virtual oral administration in rats. To ensure that a broad range of chemical structures is present among the selected substances, the properties described by 196 chemical descriptors in a chemoinformatics tool were calculated for 50,000 randomly selected molecules in the original chemical space. To allow visualization, the resulting chemical space was projected onto a two-dimensional plane using generative topographic mapping. The calculated absorbance rates of the chemicals based on cell permeability studies were found to be inversely correlated to the no-observed-effect levels for hepatoxicity after oral administration, as obtained from the Hazard Evaluation Support System Integrated Platform in Japan (r = -0.88, p < 0.01, n = 27). The maximum plasma concentrations and the areas under the concentration-time curves (AUC) of a varied selection of chemicals were estimated using two different methods: simple one-compartment models (i.e., high-throughput toxicokinetic models) and simplified physiologically based pharmacokinetic (PBPK) modeling consisting of chemical receptor (gut), metabolizing (liver), and central (main) compartments. The results obtained from the two methods were consistent. Although the maximum concentrations and AUC values of the 53 chemicals roughly correlated in the liver and plasma, inconsistencies were apparent between empirically measured concentrations and the PBPK-modeled levels. The lowest-observed-effect levels and the virtual hepatic AUC values obtained using PBPK models were inversely correlated (r = -0.78, p < 0.05, n = 7). The present simplified PBPK models could estimate the relationships between hepatic/plasma concentrations and oral doses of general chemicals using both forward and reverse dosimetry. These methods are therefore valuable for estimating hepatotoxicity.

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2004년도 춘계학술대회
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• pp.130-130
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• 2004

• Environmental Analysis Health and Toxicology
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• 제22권1호
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• pp.1-8
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• 2007

Biological monitoring, analyses of internal dose for exposure to toxicants, has been thought as one of the belt approaches for risk assessment. As the amount detected in human samples is generally very low, typically in the parts-per-bilion (ppb) or parts-per-trillion (ppt) range, analytic technologies such at HPLC, GC/MS, LC/MS, and LC/MS/MS have been continuously developed. In addition, route specific and sensitive exposure biomarkers have been developed for proper biological monitoring. PBPK modeling, particularly reverse dosimetry, has been emphasized as an useful method via interpretation of biological monitoring results for regulation of toxicants. Thus, this review is focused on the use of PBPK dosimetry models for toxicology research and risk assessment in Korea.

• 약학회지
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• 제59권4호
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• pp.151-157
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• 2015

The purpose of this study is to demonstrate how lead compounds are best optimized with the application of in silico QSAR and PBPK modeling at the early drug discovery stage. Several predictive QSAR models such as $IC_{50}$ potency model, intrinsic clearance model and brain penetration model were built and applied to a set of virtually synthesized library of the BACE1 inhibitors. Selected candidate compounds were also applied to the PBPK modeling for comparison between the predicted animal pharmacokinetic parameters and the observed ones in vivo. This novel lead optimization strategy using QSAR and PBPK modelings could be helpful to expedite the drug discovery process.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1995년도 제3회 추계심포지움
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• pp.135-136
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• 1995

Resent advances in computer technology have introduced a sophisticated capability for computing the biological fate of toxicants in a biological system. This methodology, which has drastically altered risk assessment skill in toxicology, is designed using all the mechanistic information, and all claim better accuracy with extrapolating capability Iron animal to people than conventional pharmacokinetic methods. Biologically based mathematical models in which the specific mechanistic steps governing tissue disposition(pharmacokinetics) and toxic action (pharmacodynamics) of chemicals are constructed in quantitative terms by a set of equations loading to prediction of the outcome of specific toxicological experiments by computer simulation. pharmacokinetic and pharmacodynamic models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals.

• Journal of Korean Society for Atmospheric Environment
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• 제17권E2호
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• pp.43-51
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• 2001

A report by the national research council in the United States suggested that many lung cancer deaths each year be associated with breathing radon in indoor air. Most of the indoor radon comes directly from soil beneath the basement of foundations. Recently, radon released from groundwater is found to contribute to the total inhalation risk from indoor air. This study presents the quantitative assessment of human exposures to radon released from the groundwater into indoor air. At first, a three-compartment model is developed to describe the transfer and distribution of radon released from groundwater in a house through showering, washing clothes, and flushing toilets. Then, to estimate a daily human exposure through inhalation of such radon for an adult. a physiologically-based pharmacokinetic(PBPK) model is developed. The use of a PBPK model for the inhaled radon could provide useful information regarding the distribution of radon among the organs of the human body. Indoor exposure patterns as input to the PBPK model are a more realistic situation associated with indoor radon pollution generated from a three-compartment model describing volatilization of radon from domestic water into household air. Combining the two models for inhaled radon in indoor air can be used to estimate a quantitative human exposure through the inhalation of indoor radon for adults based on two sets of exposure scenarios. The results obtained from the present study would help increase the quantitative understanding of risk assessment issues associated with the indoor radon released from groundwater.