RT Journal Article
SR Electronic
T1 In Defense of Current Concepts and Applications of Clearance in Drug Development and Therapeutics
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 187
OP 190
DO 10.1124/dmd.121.000637
VO 50
IS 2
A1 Malcolm Rowland
A1 Michael S. Roberts
A1 K. Sandy Pang
YR 2022
UL http://dmd.aspetjournals.org/content/50/2/187.abstract
AB 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 almost 50 years have been challenged with the argument that organ clearance should not be based on elimination rate, now defined by loss 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.SIGNIFICANCE STATEMENT Clearance concepts are widely applied in drug development and therapy. Historically, hepatic clearance has been defined as the ratio of rate of elimination divided by ingoing blood concentration. Recently, this approach has been challenged arguing that clearance should be referenced to blood concentration within the liver. There is no need for additional, a feature that corresponds to intrinsic clearance of the chosen clearance model, a widely accepted parameter in physiologically based pharmacokinetic (PBPK) and in vitro to in vivo extrapolation (IVIVE). There is no need for additional, confusing clearance terms, which offer no material benefit.