Journal: Toxicological Sciences

Article Title: Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

doi: 10.1093/toxsci/kfw193

Figure Lengend Snippet: Concentration Data Used in the Optimization and Validation of the Baseline DILIsym PBPK Sub-Model for Tolvaptan

Article Snippet: To more closely describe the relationship between concentration at the site of action and effect, the intracellular concentration in the HepG2 cells used in the XF Analyzer experiments was estimated using the DILIsym PBPK simulation results; the simulated liver:plasma concentration ratio was assumed to approximate the concentration ratio between the hepatocyte and the media, thus providing a scaling factor to convert the nominal media concentration to an estimated intracellular concentration.

Techniques: Concentration Assay, Biomarker Discovery

Journal: Toxicological Sciences

Article Title: Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

doi: 10.1093/toxsci/kfw193

Figure Lengend Snippet: Parameters Optimized to Data in the DILIsym PBPK Sub-Model for Tolvaptan.

Article Snippet: To more closely describe the relationship between concentration at the site of action and effect, the intracellular concentration in the HepG2 cells used in the XF Analyzer experiments was estimated using the DILIsym PBPK simulation results; the simulated liver:plasma concentration ratio was assumed to approximate the concentration ratio between the hepatocyte and the media, thus providing a scaling factor to convert the nominal media concentration to an estimated intracellular concentration.

Techniques: Clinical Proteomics

Journal: Toxicological Sciences

Article Title: Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

doi: 10.1093/toxsci/kfw193

Figure Lengend Snippet: Comparison of simulation results and in vitro data for tolvaptan- and DM-4103-induced inhibition of HepG2 oxygen consumption rate. Simulations were conducted in MITOsym and were used to identify parameter values for compound-mediated ETC inhibition that permit simulations to reproduce the in vitro data. The intracellular compound concentration was either assumed to be equivalent to the nominal media concentration or was estimated based on the liver:plasma ratio derived from simulations using the PBPK sub-model. MITOsym parameter values identified with the estimated intracellular compound concentrations were the ones translated to DILIsym and used for toxicity simulations.

Article Snippet: To more closely describe the relationship between concentration at the site of action and effect, the intracellular concentration in the HepG2 cells used in the XF Analyzer experiments was estimated using the DILIsym PBPK simulation results; the simulated liver:plasma concentration ratio was assumed to approximate the concentration ratio between the hepatocyte and the media, thus providing a scaling factor to convert the nominal media concentration to an estimated intracellular concentration.

Techniques: Comparison, In Vitro, Inhibition, Concentration Assay, Clinical Proteomics, Derivative Assay

Journal: Pharmaceutics

Article Title: Escitalopram Dose Optimization During Pregnancy: A PBPK Modeling Approach

doi: 10.3390/pharmaceutics17101341

Figure Lengend Snippet: Workflow for developing the escitalopram PBPK model. Upward arrows denote an increase, and downward arrows denote a decrease. Abbreviations: M.W., molecular weight; LogP, logarithm of octanol/water partition coefficient; pK a , negative logarithm of acid dissociation constant; B/P, blood-to-plasma ratio; fa, fraction absorbed; k a , absorption rate constant; f u,gut , fraction unbound in gut enterocytes; Q gut , Hybrid parameter representing drug absorption rate from the gut lumen, removal of drug from the enterocyte by enterocytic blood supply, and enterocyte volume; Vss, steady-state volume of distribution; K p scalar, tissue-to-plasma partition coefficient scalar; CL int , intrinsic clearance; CYP, cytochrome P450; GFR, glomerular filtration rate; NM, normal metabolizer; PM, poor metabolizer; CL PDM , Maternal-placental barrier clearance; CL PDF , placental-fetal barrier clearance.

Article Snippet: The PBPK model of escitalopram was developed using Simcyp ® PBPK simulator version 21 (Certara, Princeton, NJ, USA) to simulate pharmacokinetics in nonpregnant women, pregnant women, and the fetoplacental unit. shows the overall workflow.

Techniques: Molecular Weight, Clinical Proteomics, Filtration