There is Only One Valid Definition of Clearance: Critical Examination of Clearance Concepts Reveals the Potential for Errors in Clinical Drug Dosing Decisions

Leslie Z Benet,Jasleen K Sodhi,Ali Mesbah,George Makrygiorgos

doi:10.1208/s12248-021-00591-z

Abstract

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. There is only one valid definition of clearance. Defining organ clearance solely on the basis of systemic blood concentrations can lead to drug dosing errors when drug effect sites reside either in an eliminating organ exhibiting incremental clearance or in a non-eliminating organ where intraorgan concentration is governed by transporter actions. Attempts to predict clearance are presently hampered by the lack of recognition that what we are trying to predict is a well-stirred model clearance.

Highlights

Clinical medicine drug dosing decisions are traditionally based on pharmacokinetic clearance concepts
& Apparent clearance measurements based on systemic drug concentrations may not yield correct drug dosing decisions for those drugs where pharmacodynamic effects are a function of intraorgan drug concentrations and when intraorgan concentrations decrease incrementally or are affected by transporters
Pharmacokinetics and the use of clearance was a revolutionary advance in therapeutics allowing rational decisions about the appropriate dose and dosing interval, and how these doses should be adjusted as a function of disease states when additional drugs are dosed leading to clearance changes and dose adjustments necessary because of pharmacogenomic and physiologic variance

Summary

INTRODUCTION

Clinical medicine drug dosing decisions are traditionally based on pharmacokinetic clearance concepts. Measured systemic drug concentrations (Csystemic) are most often used in making these drug dosing decisions because of its direct relationship with clearance (CL) as given by Amount eliminated per unit time 1⁄4 CL⋅Csystemic ð1Þ where the amount eliminated per unit time is measured in units of mass/time, Csystemic in units of mass/volume, and the units of CL are volume/time. Clearance is a measure of the volume of systemic fluid (e.g., blood, plasma) flowing through the body’s organs of elimination that is completely removed of the drug per unit time. Note that in vivo in humans, clearance cannot be calculated using Eq 1, since it is not possible to measure the amount eliminated per unit time where elimination is via metabolism or biliary excretion, except at steady state. For renal clearance where the amount eliminated per unit time in the urine is

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CONCLUSIONS

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