Drug Metab Dispos. 2021 Sep;49(9):736-742. doi: 10.1124/dmd.121.000409. Epub 2021 Jun 16.

Impact of Interindividual Differences in Plasma Fraction Unbound on the Pharmacokinetics of a Novel Syk Kinase Inhibitor in Beagle Dogs.

Drug metabolism and disposition: the biological fate of chemicals

Andy Pike, Barry Jones, Roshini Markandu, Daniel O'Neill, Putra

PMID: 34135088 DOI: 10.1124/dmd.121.000409

Abstract

Inconsistencies in pharmacokinetic parameters between individual animals in preclinical studies are a common occurrence. Often such differences between animals are simply accepted as experimental variability rather than as indications of specific differences in animal phenotype that could lead to a different interpretation of the data. The fraction unbound in plasma is one factor influencing pharmacokinetic parameters and is typically determined using pooled plasma from multiple animals, making the assumption that there is limited population variance. However, this assumption is not often tested and may not hold true if there are polymorphisms affecting binding or variation in the concentrations of individual plasma proteins that could give rise to different fraction unbound phenotypes in individual animals. During profiling of a novel Syk inhibitor, AZ8399, striking interindividual differences in total plasma clearance and volume of distribution were observed between dogs consistent with differences in fraction unbound between animals. Determination of the fraction unbound showed a ∼5-fold difference in fraction unbound between the animals in the study. Broader analysis of individual dogs across a colony demonstrated a correlation between individual animal fraction unbound with total plasma clearance and volume of distribution. The concentrations of the common drug-binding proteins albumin and

Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Publication Types

• Journal Article
• Research Support, Non-U.S. Gov't