Figure 4.

Incorporation of the validity check for the canonical approach into in vitro‐in vivo extrapolation for clearance (CL). If K _M of the drug is not 10‐fold higher than the hepatic concentration of its major CYP (E _T), the canonical approach cannot capture the saturation of metabolism caused by the binding of a significant fraction of the substrate to the enzyme. Thus, to extrapolate ${\text{CL}}_{\text{int}}^{\text{liver}}$ from ${\text{CL}}_{\text{int}}^{\text{vitro}}$ , the new approach should be used, which incorporates the saturation of metabolism. See Supplementary Table S3 and Methods for the detailed estimation procedure for the hepatic E _T. ${\text{CL}}_{\text{int}}^{\text{liver}}$ , intrinsic clearance of the liver; ${\text{CL}}_{\text{int}}^{\text{vitro}}$ in vitro intrinsic clearance of the liver; K _M, Michaelis‐Menten constant; V _max, maximal rate of metabolism.