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. 2020 Sep 25;9(10):571–583. doi: 10.1002/psp4.12553

Figure 2.

Figure 2

Sensitivity analyses of simulated renal clearance (CLr, in mL/min) at multiple stages of chronic kidney disease (CKD) reflected as varying glomerular filtration rate (GFR, in mL/min) using proportional model (shown in blue‐green) vs. adaptive model (shown in yellow‐red). Three sets of sensitivity analyses were conducted, (1) CLr of neutral drugs with varying permeability values (P app = 1–100 × 10‐6 cm/s, all values shown are in 10‐6 cm/s) but a constant plasma unbound fraction (f u,p = 1) and peritubular renal blood flow (RBF = 1,000 mL/min, the average of healthy human subjects) were simulated using proportional model (a), adaptive model (b), and both models (c) across a wide range of GFR values from 5 mL/min to 120 mL/min, (2) renal clearances of highly permeable neutral drugs (P app = 100 × 10‐6 cm/s) with varying f u,p (0.1–1) but a constant peritubular RBF (1,000 mL/min) were simulated using the proportional model (d), the adaptive model (e), and both models (f) across a range of GFR from 5 mL/min to 120 mL/min, (3) CLr of a highly permeable neutral drugs (P app = 100 × 10‐6 cm/s) with varying peritubular RBF (300–1,000 mL/min) but a constant f u,p (1) were simulated using proportional model (g), adaptive model (h), and both models (i) across a range of GFR from 5 mL/min to 120 mL/min. In panel a (proportional model), the decrease in CLr between GFR of 120 mL/min and GFR of 5 mL/min is 24‐fold for all permeability values. In contrast, in panel b (adaptive model), the CLr decreases by 22‐fold for a drug with a permeability of 1 between GFR of 120 mL/min and GFR of 5 mL/min, whereas the CLr decreases by 1.5‐fold for a drug with a permeability of 100 between GFR of 120 mL/min and GFR of 5 mL/min, demonstrating a high sensitivity of the CLr reduction to drug permeability.