Impact of interindividual differences in plasma fraction unbound on the pharmacokinetics of a novel Syk kinase inhibitor in beagle dogs

Abstract

Inconsistencies in pharmacokinetic parameters between individual demonstrated a correlation between individual animal fraction animals in preclinical studies are a common occurrence. Often such unbound with total plasma clearance and volume of distribution. The differences between animals are simply accepted as experimental var-concentrations of the common drug-binding proteins albumin and a1-iability rather than as indications of specific differences in animal pheacid glycoprotein in plasma were determined, and a1-acid glycopronotype that could lead to a different interpretation of the data. The tein levels were found to correlate with fraction unbound. Finally, sin-fraction unbound in plasma is one factor influencing pharmacokinetic gle-nucleotide polymorphisms were identified at c.502 and c.522 of parameters and is typically determined using pooled plasma from exon 5 of the dog a1-acid glycoprotein gene that may be correlated to multiple animals, making the assumption that there is limited populathe a1-acid glycoprotein concentration phenotype observed. tion variance. However, this assumption is not often tested and may not hold true if there are polymorphisms affecting binding or variation SIGNIFICANCE STATEMENT in the concentrations of individual plasma proteins that could give The current work demonstrates the potential for significant interindirise to different fraction unbound phenotypes in individual animals. vidual differences in plasma fraction unbound in beagle dogs and During profiling of a novel Syk inhibitor, AZ8399, striking interindividgoes on to examine the underlying cause for the compound described. ual differences in total plasma clearance and volume of distribution The findings suggest that the application of a population mean value were observed between dogs consistent with differences in fraction of fraction unbound generated from a pooled sample may not always unbound between animals. Determination of the fraction unbound be appropriate and could introduce significant errors in scaling of showed a ̴5-fold difference in fraction unbound between the animals in vitro clearance values, PBPK understanding, and interpretation of in the study. Broader analysis of individual dogs across a colony PKPD or toxicokinetic data in the context of unbound concentrations.