Figure 5.

Simulation (Sim) and verification of renal drug clearance (CL_r) of six permeable and highly renally reabsorbed compounds at multiple stages of chronic kidney disease (CKD) reflected by varying glomerular filtration rate (GFR). Observed (Obs) CL_r data of the test compounds are from individual subjects when available and are shown as black open circles. If only group mean data were available, data are shown as black solid squares with 95% confidence interval as the error bar. The simulated CL_r of different test compounds at varying stages of CKD are shown with red curves for the adaptive model and blue dashed curves for the proportional model (a–c, g–i). The performance of adaptive and proportional model was evaluated at CKD stages 4 and 5 (GFR ≤ 30 mL/min) using calculated absolute fold‐error (AFE)_A (shown in red) and AFE_P (shown in blue), respectively (d–f, j–l). The plasma unbound fraction (f _u,p) and observed CL_r data of pefloxacin a, d, metronidazole b, e, and minocycline c, f, digitoxin g, j, cicletanine h, k, and pirfenidone I, l were collected from literature and summarized in Table S2 . The apparent permeability (P _app) values of pefloxacin, metronidazole, and minocycline were experimentally determined, whereas the P _app values of other drugs were optimized using the f _u,p and observed CL_r in healthy subjects, assuming no active secretion. The same optimized P _app values were used for extrapolated simulations at varying stages of CKD. The simulation results in linear plot are shown in the Figure S1 .