A myth of the well-stirred model: Is the well-stirred model good for high clearance drugs?

Understanding the rationale of the well-stirred model (WSM), borrowed from chemical engineering, has been ongoing through the history of pharmacokinetics (PK) as an independent discipline. Extensive arguments around the WSM and 1977′s lidocaine data re-emerged recently. It was proposed that Pang and Rowland\u27s lidocaine data analysis was confounded by four intermingled confounding factors which may lead to contradictory conclusions or inconclusive dilemma. This re-visit of 1977′s lidocaine data analysis was challenged by Pang and coauthors. This commentary is our responses to their comments focusing on the lidocaine data analysis and the IVIVE by the WSM. In addition, the disadvantage of applying the well-stirred model in drug-drug interaction (DDI) prediction and a theoretical dilemma in the commonly used whole-body physiologically based pharmacokinetic (PBPK) models were discussed