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Full physiologically-based biokinetic model framework used within Simcyp ® to simulate the plasma and organ tissue concentration-time profile, including the associated permeabilitylimited liver model used to describe the hepatic distribution of rosuvastatin between the vascular space (VS), extracellular water (EW) and intracellular water (IW) compartments The VS consists of blood supply arriving from the portal vein and hepatic artery. Distribution of the unbound, unionized compound between the VS and EW is instantaneous, while the distribution between the EW and IW would depend on the rate of passive diffusion (CLPassiveDiffusion), active uptake (CLUptake,Basolateral), and active efflux (CLEfflux,Basolateral). Elimination of the unbound compound from the IW would depend on the rate of metabolism (CLMetabolism) and rate of biliary excretion (CLBiliaryExcretion). The fraction unbound in the intracellular water (fuIW) is influenced by the binding of the compound to intracellular neutral phospholipids (NP), neutral lipids (NL), and acidic phospholipids (AP). The three equilibrium processes refer to (a) binding to plasma protein, NP, NL and AP, (b) ionization of the compound, and (c) instantaneous equilibrium of unbound, unionized compound between the VS and EW.
Source publication
Advancements in physiologically-based biokinetic (PBK) modelling, in vitro-to--in vivo extrapolation (IVIVE) methodologies and development of permeability-limited biokinetic models have allowed for predictions of tissue drug concentrations without utilizing in vivo animal or human data. However, there is a lack of in vivo human tissue concentration...
Contexts in source publication
Context 1
... models divide the organ into three compartments: intracellular, extracellular and vascular space. An example of a permeability-limited model for the liver is illustrated in Figure 1. Typically, it is assumed that blood capillaries do not present a barrier to small molecule solutes; hence the unbound, unionized compound undergoes instantaneous equilibrium between the vascular and extracellular space. ...
Context 2
... PBK model was used to describe the perfusion-limited distribution of RSV into various organ compartments. The Rodgers and Rowland (2007) tissue composition method was used to predict the tissue-to-plasma equilibrium distribution ratios for each organ compartment. The permeability-limited liver (PerL) model was incorporated into the full PBK model (Fig. 1) to describe the permeability-limited distribution of RSV into the liver ( Jamei et al., 2014). The PerL model divides the liver into 3 compartments: intracellular water (IW), extracellular water (EW) and vascular space (VS). It is assumed that unbound, unionized compounds within the EW and VS are in instantaneous equilibrium, and the ...
Citations
... A pesar de que los biorreactores producen datos empíricos, las ecuaciones biocinéticas y de balance de materia brindan los instrumentos necesarios para convertir los datos empíricos en algo específico: parámetros biocinéticos. Los modelos biocinéticos pueden ser parametrizados con medidas biocinéticas in vitro para permitir la extrapolación in vitro-in vivo para la predicción de parámetros del cuerpo [3] . Sumado a esto, los datos biocinéticos juegan un rol importante en el proceso de obtener estimaciones potencialmente de humanos, que permiten su propia comparación para evaluar la exposición al riesgo [4] . ...
Bioreactors are one of the greatest solutions to the main diseases in Mexico in tissue engineering applications, they are used as a tool to propose different cell reproduction techniques as they provide different parameters. Biokinetic parameters are dictated by mathematics to provide operating conditions. This paper proposes a dynamic math-ematical model design to determine the behavior of liver cells, protein and substrate production in a bioreactor. The proposed model returns as a result the prediction of performance of different variables over time. Relevant biokinetic parameters found are YXS = 2.94 g/g, YPS = 5.46 g/g, and μmáx = 1.84 1/h. Additionally, a parametric sen-sitivity analysis was executed to detect parameters that retain effects on biomass and product concentrations. The parameters are YXS, α, and β for biomass, and μmáx, YXS, and KPS for product concentrations. As an element of this study, diverse simulations were employed to determine performance at different initial substrate concentrations. The results establish that, the higher initial substrate concentration is, the lower the yield within the first eight days. Afterward yields are almost identical for all initial substrate concentrations.
Purpose
This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics.
Methods
A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, ¹¹C-metformin, morphine and the glucuronide metabolite of morphine).
Results
PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of ¹¹C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72).
Conclusion
A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.
Tissue engineering has emerged as a tool to propose solutions to the main diseases that cause death in Mexico, achieving different cell reproduction techniques such as the use of bioreactors. Mathematics can determine and collect biokinetic parameters, providing the necessary skills to optimize different operating conditions. Therefore, this study aims to design a dynamic mathematical model that describes the behavior of liver cells, protein, and substrate production in a bioreactor. The results showed that the proposed model can predict the behavior of different variables over time. Some of the biokinetic parameters found are YXS = 2.94 gx/gs, YPS = 5.46 gp/gs, and μmáx = 1.84 1/h. Contrastingly, a parametric sensitivity analysis was carried out to find parameters that have the greatest effect on the concentration of biomass and product. The parameters are YXS, α and β for biomass concentration, and μmáx, YXS and KPS for product concentration. As part of the study, different simulations were carried out to determine the performance at different initial substrate concentrations. The results show that the higher the initial substrate concentration, the lower the yield within the first 8 days. After this time, the yields are similar for all types of initial substrate concentration.KeywordsBiokineticsBiomassBiomathematicsBioreactorGlucoseHepatocytesMonodProductSubstrate
