Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

doi: 10.1124/jpet.116.237438

Figure Lengend Snippet: Workflow of the development and application of the PBPK kidney model for digoxin.

Article Snippet: All simulations presented herein were performed using the SimCYP population-based PBPK simulator software, version 14, release 1 (SimCYP, Sheffield, UK) ( ; ).

Techniques:

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

doi: 10.1124/jpet.116.237438

Figure Lengend Snippet: Mean simulated digoxin plasma concentration time profiles (intravenous administration of 1 mg digoxin) for intermediate PBPK models used during development of the mechanistic kidney model. CL R defined by a single input value (136.1 ml/ min) based on the literature analysis (orange line) and CL R simulated using the mechanistic kidney model, accounting for only glomerular filtration (purple line), glomerular filtration and reabsorption (turquoise line), or glomerular filtration, reabsorption, and active secretion (blue line).

Article Snippet: All simulations presented herein were performed using the SimCYP population-based PBPK simulator software, version 14, release 1 (SimCYP, Sheffield, UK) ( ; ).

Techniques: Concentration Assay, Filtration

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research

Article Title: Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics

doi: 10.1158/1078-0432.CCR-14-0791

Figure Lengend Snippet: Schemes of model structures. A, parent–metabolite joint pharmacokinetic model. Ka, first-order absorption rate constant; Vp/F, apparent volume of distribution for the parent drug; CLpm/F, apparent clearance for conversion of the parent drug to metabolite; CLp/F, apparent clearance of the parent drug via renal excretion and additional liver metabolism; Vm, volume of distribution for the metabolite; CLm, clearance of the metabolite. B, whole-body PBPK model integrated with a mechanistic kidney module for prediction of veliparib pharmacokinetic profiles. The mechanistic kidney module illustrates the major processes governing drug transfer from blood to the urine: passive diffusion (passive diffusion clearance, CLpd), basolateral transporters-mediated uptake from the blood into proximal tubule cells (uptake transporter intrinsic clearance, CLint,T,up), and apical transporters-mediated efflux from the tubule cells into urine (efflux transporter intrinsic clearance, CLint,T,eff). The effects of the inhibitor (i.e., quinidine or cimetidine) on the CYP2D6 metabolism or OCT2 uptake activity was simulated in a dynamic fashion by linking the inhibitor model (i.e., limited PBPK model for quinidine or whole-body PBPK model for cimetidine) to veliparib PBPK model.

Article Snippet: Using the population-based PBPK software Simcyp Simulator (version 13.1; Simcyp Ltd.), a whole-body PBPK model integrated with a mechanistic kidney module ( ) was developed to simulate veliparib plasma concentration–time profiles in an existing virtual Caucasian population with normal renal function (i.e., “NEurCaucasian” population).

Techniques: Diffusion-based Assay, Activity Assay

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research

Article Title: Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics

doi: 10.1158/1078-0432.CCR-14-0791

Figure Lengend Snippet: Drug-dependent parameters used in veliparib PBPK model with a mechanistic kidney module

Article Snippet: Using the population-based PBPK software Simcyp Simulator (version 13.1; Simcyp Ltd.), a whole-body PBPK model integrated with a mechanistic kidney module ( ) was developed to simulate veliparib plasma concentration–time profiles in an existing virtual Caucasian population with normal renal function (i.e., “NEurCaucasian” population).

Techniques: Molecular Weight, Formulation, Recombinant, Clinical Proteomics, Concentration Assay, Activity Assay, Diffusion-based Assay

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research

Article Title: Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics

doi: 10.1158/1078-0432.CCR-14-0791

Figure Lengend Snippet: Physiologically based pharmacokinetic modeling and simulation. A and B, observed and predicted single-dose and steady-state plasma concentration–time profiles of veliparib. Simulations of 10 virtual trials with 10 subjects in each were performed in Caucasian population with normal renal function, following oral administration of veliparib as either a single dose of 40 mg or twice daily 40 mg for 15 days. Observed data were obtained from 8 patients with Caucasian cancer with normal renal function receiving a single dose of 40 mg or twice daily dosing. The thick black line represents overall mean predicted concentration–time profile for the virtual population (n = 100); dotted and dash line represent the 95th and 5th percentile, respectively; and the symbols represented the observed veliparib concentrations. C, AUC ratios of veliparib under various scenarios. D, sensitivity analysis showing the impact of OCT2 activity (intrinsic uptake clearance) on veliparib plasma pharmacokinetic parameters (Cmax, maximum plasma concentration; Tmax, time to reach Cmax; AUC, area under the concentration–time curve; CL/F, oral clearance) and mechanistic kidney model parameters (CLr, renal clearance; Ae, accumulated amount of unchanged drug excreted in the urine; Akc-max, maximum amount of drug accumulated in the kidney proximal tubule cells). Sensitivity analysis was performed with OCT2 intrinsic uptake clearance varying from 0.1 to 20 μL/min/106 cells whereas ABCB1 intrinsic efflux clearance fixing at 2 μL/min/106 cells.

Article Snippet: Using the population-based PBPK software Simcyp Simulator (version 13.1; Simcyp Ltd.), a whole-body PBPK model integrated with a mechanistic kidney module ( ) was developed to simulate veliparib plasma concentration–time profiles in an existing virtual Caucasian population with normal renal function (i.e., “NEurCaucasian” population).

Techniques: Clinical Proteomics, Concentration Assay, Activity Assay