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: The effect of 24 h treatment of tolvaptan, DM-4103 and DM-4107 on basal mitochondrial respiratory function (fmoles O 2 /min/cell) in HepG2 cells. Cells were treated with control media or compound in a 5-point dose response regimen (tolvaptan at: 0.01, 0.1, 1, 20, and 50 µM or DM-4103 or DM-4107 at: 1, 20, 50, 100 and 200 µM) for 24 h prior to respirometry experiments. Oxygen consumption rate (OCR) results were normalized to cell number. Data are presented as the average ± SEM for 3 independent experiments. Statistical significance is denoted by an asterisk (* P ≤ .05) for one-way ANOVA with Dunnett’s multiple comparison test to compare each concentration to control for a given compound. Two-way ANOVAs with a Bonferonni multiple comparison test was used to compare compounds: # P ≤ .05 (DM-4103 vs DM-4107); @ P ≤ .05 (tolvaptan vs DM-4103); & P ≤ .05 (tolvaptan vs DM-4107).

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques: Control, Comparison, Concentration Assay

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 increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

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: Parameters Changed between the Renally Sufficient and the Renally Impaired SimPops

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques: Activity Assay

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: List of Mechanistic Investigation Simulations and the Mechanisms that Were Turned On and Off for Each Simulation of Tolvaptan Administered 90/30 mg Daily for 180 Days

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques:

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: List of Parameters Included in the SimPops Used for This Investigation and The Ranges For Each Parameter Relative to Their Average Values

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques:

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 between single dose clinical data for 30 mg, dark red, 60 mg, cyan, and 120 mg, dark green , and range of Renally Sufficient SimPops simulation results for (a) tolvaptan plasma concentrations; (b) DM-4103 plasma concentrations (note: data from the 120 mg study were unavailable for this analyte; see ); (c) DM-4107 plasma concentrations. Dark circles represent the average of the clinical data; stars represent the maximum and minimum value measured in the clinical trial. Simulation results for the 30 mg study are in red, simulation results for the 60 mg study are in blue, and simulation results for the 120 mg study are in green.

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques: Comparison, 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 between Renally Sufficient SimPops and day 21 tolvaptan plasma concentrations after 90/30 mg split daily dosing ( Boertien et al. , 2013 ). The clinical data are represented by symbols (black squares) whereas the simulation results for individual simulated patients are represented by solid lines.

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques: Comparison, 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 between Renally Impaired SimPops and day 21 tolvaptan plasma concentrations after 90/30 mg split daily dosing ( Boertien et al. , 2013 ). The clinical data are represented by symbols (black squares) whereas the simulation results for individual simulated patients are represented by solid lines.

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques: Comparison, 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: DILIsym Toxicity Parameter Values for Tolvaptan Toxicity Simulations

Article Snippet: To increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

Techniques: Inhibition

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 increase confidence that the DILIsym parameter values for tolvaptan reasonably captured “safe” tolvaptan scenarios (in addition to the DILI scenarios of interest), the 60 mg daily dose for 60 days tolvaptan dosage regimen was simulated in the Renally Sufficient SimPops.

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