Xenografted Tumors Share Comparable Fraction Unbound and Can Be Surrogated by Mouse Lung Tissue

Min Wang; Sandip Kuldharan; Aravind Shenoy; Satyanarayana Reddy; Karen Rex; Tao Osgood; Jan Wahlstrom; Upendra P Dahal

doi:10.1124/dmd.124.001698

Xenografted Tumors Share Comparable Fraction Unbound and Can Be Surrogated by Mouse Lung Tissue

Drug Metab Dispos. 2024 Apr 26:DMD-AR-2024-001698. doi: 10.1124/dmd.124.001698. Online ahead of print.

Authors

Min Wang¹, Sandip Kuldharan², Aravind Shenoy², Satyanarayana Reddy², Karen Rex¹, Tao Osgood¹, Jan Wahlstrom³, Upendra P Dahal⁴

Affiliations

¹ Amgen, United States.
² Syngene, India.
³ Pharmacokinetics & Drug Metabolism, Amgen, Inc, United States.
⁴ PKDM, Amgen, United States udahal@amgen.com.

PMID: 38670798
DOI: 10.1124/dmd.124.001698

Abstract

Free (unbound) drug concentration at the site of action is the key determinant of biological activity since only unbound drugs can exert pharmacological and toxicological effects. Unbound drug concentration in tumors for solid cancers is needed to understand/explain/predict pharmacokinetics (PK), pharmacodynamics (PD), and efficacy relations. Fraction unbound (f_u) in tumors is usually determined across several xenografted tumors derived from various cell lines in the drug discovery stage, which is time-consuming and a resource burden. In this study, we determined the f_u values for a set of diverse compounds (comprising acid, base, neutral, zwitterion, and covalent drugs) across five different xenografted tumors and five commercially available mouse tissues to explore the correlation of f_u between tumors and the possibility of surrogate tissue(s) for tumor f_u (f_u,tumor) determination. The cross-tumor comparison showed f_u,tumor values across tumors are largely comparable, and systematic tissue vs. tumor comparison demonstrated only lung tissue had comparable f_u to all five tumors (f_u values within 2-fold change for >80% compounds in both comparisons). These results indicated mouse lung tissue can be used as a surrogate matrix for f_u,tumor assay. This study will increase efficiency in f_u,tumor assessment and reduce animal use (adapting the 3Rs principle: replace, reduce, and refine) in drug discovery Significance Statement The free drug concept is a well-accepted principle in drug discovery research. Currently, f_u,tumor is determined in several tumors derived from different cell lines to estimate free drug concentrations of a compound. The results from this study indicated f_u,tumor across xenografted tumors are comparable and f_u,tumor can be estimated using a surrogate tissue, mouse lung. The results will increase efficiency in f_u,tumor assessment and reduce animal use in drug discovery.

Keywords: pharmacodynamics; pharmacokinetic; protein binding.