In defense of current concepts and applications of clearance in drug development and therapeutics .

Clearance is one of the most widely quoted and applied pharmacokinetic concepts in drug development and therapy. Its foundations and associated models of drug elimination are well embedded and accepted within the scientific community. Recently, however, the prevailing views that have held us in good stead for the past 50 years have been challenged with the argument that organ clearance should not be based on elimination rate, now defined by extraction across the liver divided by incoming or systemic concentration, as in current practice, but rather by the mean concentration of drug within the blood in the organ, which is model dependent. We argue that all needed parameters already exist, and that the proposed new approach to organ clearance is confusing and unnecessary. Clearance concepts are widely applied in drug development and drug therapy. Historically, hepatic clearance has referenced rate of elimination to the ingoing concentration. Recently, this approach has been challenged arguing that clearance should be referenced to the concentration within the liver, a feature that corresponds to the intrinsic clearance of the chosen clearance model, a widely accepted parameter applied to PBPK and IVIVE. There is no need for additional clearance terms, which are confusing and offer no material benefit.