Can In Vitro-In Vivo Extrapolation Be Successful? Recognizing the Incorrect Clearance Assumptions

Area of Science:

• Pharmacokinetics
• Drug Metabolism and Disposition
• Biopharmaceutics

Background:

• Published in vitro-in vivo extrapolation (IVIVE) predictability for human clearance is consistently poor.
• Existing IVIVE approaches and fundamental clearance concepts require critical re-examination from theoretical and experimental viewpoints.

Purpose of the Study:

• To critically analyze the theoretical and experimental basis of in vitro-in vivo extrapolation (IVIVE) for human drug clearance.
• To identify and elucidate misconceptions in current clearance concepts and IVIVE methodologies.

Main Methods:

• Theoretical examination of drug clearance concepts.
• Critical analysis of commonly employed in vitro-in vivo extrapolation (IVIVE) approaches.
• Experimental perspective on the predictability of human clearance.

Main Results:

• Identified 10 misconceptions and poorly understood aspects of drug clearance.
• Concluded that there is no theoretical basis for the success of current in vitro-in vivo extrapolation (IVIVE) methods.
• Demonstrated that published human drug clearance values are not arterial clearances and the well-stirred model equation lacks validity.

Conclusions:

• The intrinsic clearance value from in vitro incubations is an arterial intrinsic clearance.
• There is no theoretical basis to relate arterial intrinsic clearance to whole-body arterial clearance for IVIVE.
• No published data support the prediction of in vivo organ clearance from in vitro metabolic clearance, and the albumin-mediated hepatic uptake hypothesis is invalid.