Predicting oral clearance in humans: how close can we get with allometry?

Area of Science:

• Pharmacokinetics
• Drug Development
• Allometric Scaling

Background:

• Oral clearance (CL/F) is a critical pharmacokinetic parameter for determining safe and effective oral drug doses.
• Accurate prediction of oral pharmacokinetic parameters, including CL/F, is essential but limited by a scarcity of published scaling studies.
• Understanding CL/F aids in selecting appropriate doses for early-phase clinical trials.

Purpose of the Study:

• To evaluate and compare the predictive performance of different allometric scaling approaches for human oral clearance (CL/F) and oral area under the plasma concentration-time curve (AUC).
• To identify the most effective allometric methods for predicting key pharmacokinetic parameters in drug development.

Main Methods:

• Four allometric approaches were assessed: simple allometry (SA), rule of exponents, unbound CL/F, and unbound fraction corrected intercept method (FCIM).
• Twenty-four diverse compounds from Johnson and Johnson Pharmaceutical Research and Development were used for evaluation.
• CL/F was predicted using these methods, and oral AUC was subsequently estimated based on the predicted CL/F.

Main Results:

• The unbound CL/F approach, combined with maximum lifespan potential or brain weight as correction factors using the rule of exponents, yielded the most successful CL/F and oral AUC predictions.
• The unbound CL/F approach demonstrated superior predictive accuracy when the simple allometry exponent ranged between 0.5 and 1.2.
• The FCIM proved to be the preferred method when the simple allometry exponent was outside this range (<0.50 or >1.2).

Conclusions:

• Selecting appropriate allometric approaches based on simple allometry exponents enabled prediction of CL/F and oral AUC within a 2-fold error for a high percentage of compounds (79% for CL/F, 83% for AUC).
• This study highlights the utility of specific allometric scaling strategies in accurately predicting human oral pharmacokinetics, supporting efficient drug development.