The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model  Helen Musther, Matthew D. Harwood, Jiansong Yang, David B. Turner, Amin Rostami-Hodjegan, Masoud Jamei  Journal of Pharmaceutical Sciences  Volume 106, Issue 9, Pages 2826-2838 (September 2017) DOI: 10.1016/j.xphs.2017.05.003 Copyright © 2017 American Pharmacists Association® Terms and Conditions

Figure 1 Comparison of simulated and observed tissue concentration profiles after a single intravenous dose of diazepam (1.2 mg/kg) (a-j). Observed data given as solid triangles, simulations using observed clearance and predicted Vss given as dashed lines, and IVIVE simulations using RHep CLint given as solid lines. Journal of Pharmaceutical Sciences 2017 106, 2826-2838DOI: (10.1016/j.xphs.2017.05.003) Copyright © 2017 American Pharmacists Association® Terms and Conditions

Figure 2 Comparison of simulated and observed plasma concentration–time profiles after intravenous dosing at (a) 0.5 mg/kg, (b) 1 mg/kg, and (c) 2 mg/kg metoprolol. Observed data given as solid triangles, simulations using observed Vss in a minimal PBPK model and observed clearance given as dotted lines, simulations using a Rodgers and Rowland predicted Vss in a full PBPK model and observed clearance given as dashed lines, and IVIVE simulations using a Rodgers and Rowland predicted Vss in a full PBPK model and rat liver microsomal CLint given as solid lines. Journal of Pharmaceutical Sciences 2017 106, 2826-2838DOI: (10.1016/j.xphs.2017.05.003) Copyright © 2017 American Pharmacists Association® Terms and Conditions

Figure 3 Comparison of simulated and observed plasma concentration–time profiles after oral dosing at (a) 1 mg/kg, (b) 2 mg/kg, and (c) 5 mg/kg metoprolol. Observed data given as solid triangles, simulations using a first-order absorption model and RLM and RIMe CLint are given as dashed lines, the ADAM model with RLM and RIMe CLint with gastric emptying rate at 0.25 h given as solid lines, and ADAM model with adjusted gastric emptying (0.11 h) given as a dot–dashed line. ADAM model with adjusted gastric emptying and Km-Vmax data are shown as dotted line. Journal of Pharmaceutical Sciences 2017 106, 2826-2838DOI: (10.1016/j.xphs.2017.05.003) Copyright © 2017 American Pharmacists Association® Terms and Conditions

Figure 4 Comparison of simulated and observed plasma concentration–time profiles after a single intravenous dose of midazolam (5 mg/kg). Observed data given as solid triangles, simulations using observed clearance and predicted Vss given as dotted lines, IVIVE simulations using rat liver microsomal CLint given as solid lines and simulations using RHep CLint given as dashed lines. Journal of Pharmaceutical Sciences 2017 106, 2826-2838DOI: (10.1016/j.xphs.2017.05.003) Copyright © 2017 American Pharmacists Association® Terms and Conditions

Figure 5 Comparison of simulated and observed plasma concentration–time profiles after a single oral dose of midazolam (15 mg/kg). Observed data given as solid triangles, simulations using the first-order absorption and Qgut model with IVIVE RHep/RIMe CLint elimination given as a dashed line, simulations using observed CLpo with the ADAM model given as the dotted line, and IVIVE RHep/RIMe CLint ADAM simulations given as a solid line. Journal of Pharmaceutical Sciences 2017 106, 2826-2838DOI: (10.1016/j.xphs.2017.05.003) Copyright © 2017 American Pharmacists Association® Terms and Conditions