Supplemental Information for
Physiologically- Based Pharmacokinetic Models for Everolimus and Sorafenib in Mice
Dipti K. Pawaskar1, Robert M. Straubinger 1,2, Gerald J. Fetterly3, Bonnie H. Hylander4, Elizabeth A. Repasky4, Wen W. Ma 3, and William J. Jusko1.
1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York 14260 and
Departments of 2Cancer Pharmacology and Therapeutics, 3Medicine, and 4Immunology, Roswell Park Cancer Institute, Buffalo, NY, 14263
Table S1: Blood flow rates and organ volumes.Organ (symbol) / Blood flowb (mL/min) / Volume (ml)a,b,c or Mass (g)
Blood (Cpl) / 11a / 1.5
Lungs (Clu) / 11 / Measured
Fat (Cf) / 0.55 / 1.10
Kidneys (Ckid) / 1.01 / Measured
Liver (Cliv) / 1.78 / Measured
Brain (Cbr) / 0.38 / Measured
Muscle (Cmu) / 1.75 / 7.92
Pancreas (Cpan) / 0.10 / Measured
Skin (Csk) / 0.63 / 2.94
Spleen (Csp) / 0.05 / Measured
Gut (Cgi) / 1.41 / 3.45
Tumor (Ctu) / 0.017 / Estimated
aGjedde et al [10]
b Davies and Morris [23]
c Brown et al [12]
Fig. S1 Goodness-of-fit plots for plasma and tissues from the final PBPK model for everolimus in mice. (a) Individual predicted response vs. observed response, (b) Weighted residuals vs. individual predicted response
a
b
Fig.S1a and b depict diagnostic plots for everolimus in plasma and tissues. It appears from the observed vs predicted graphs that the model captured the plasma concentrations reasonable well except for a few high concentration data where the model over predicts. The concentrations in brain, adipose tissue, lungs and muscle were obtained only from one study and well described by the model. The concentrations in kidneys, liver, pancreas, spleen, skin and GI are well characterized as indicated by all the data points lying close to the line of identity.
Fig.S2 Goodness-of-fit plots for plasma and tissues from the final PBPK model for everolimus Sorafenib in mice. (a) Individual predicted response vs. observed response, (b) Weighted residuals vs. individual predicted response
a
b
Fig.S2. a and b are diagnostic plots for the sorafenib concentrations in plasma and tissues. The observed vs predicted plots for plasma and tissues indicate how well the model can predict the observed concentrations. Sorafenib concentrations in plasma are well described by this model. The concentrations in the kidneys, liver and spleen are well characterized by the model. The variability in the brain, adipose, muscle, skin and pancreas is high. The variability in the GI predictions is because of it being the site of drug administration. The plots for residuals vs predicted concentrations do not exhibit any bias in the model.