Strain-Dependent Variability of Early Discovery Small Molecule Pharmacokinetics in Mice: Does Strain Matter?

Drug discovery programs routinely perform pharmacokinetic (PK) studies in mouse to prioritize lead compounds based on anticipated exposure-efficacy and exposure-toxicity relationships. Due to logistical and/or technical issues, the strain of mouse in early discovery PK studies may not always match the strain in toxicity or efficacy studies. This elicits the question: do appreciable strain-dependent differences in PK parameters exist to an extent that would warrant conducting PK studies in a strain that matches efficacy and toxicity models? To understand the impact that strain may have on PK parameters, we selected 8 marketed drugs with well characterized absorption, distribution, metabolism, and excretion properties and diverse structures to perform PK studies in three common mouse strains (BALB/c, C57BL/6, and CD-1). Some statistical strain-dependent differences were observed, however, we found good general agreeance of PK between strains: 88%, 100%, 75%, and 88% of compounds were within two-fold across strains for Cl, Vss, t1/2, and F, respectively. Overall, we recommend that an approach using a single strain of mouse is appropriate for discovery screening PK studies, provided that proper caution is exercised. SIGNIFICANCE STATEMENT: Pharmaceutical research programs routinely execute mouse PK studies to characterize PK properties of compounds as a filtering criterion to advance candidates through the pipeline as well as to support efficacy and toxicology studies. The mouse strain in discovery PK studies may not match the strain in efficacy and tox studies. Currently, there is gap in the literature addressing if differences in PK parameters across mouse strains exist such that multiple PK studies are warranted. The results from this study indicated that the PK properties of clinically used drugs between mouse strains are within an acceptable range such that single strain PK is appropriate. The American Society for Pharmacology and Experimental Therapeutics.