A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

• DOI: 10.1371/journal.pbio.3001624
• Publication Date: 2022-05-26T17:26:20Z
• Authors: Dharaminder Singh; Sudhir P. Deosarkar; Elaine Cadogan; Vikki Flemington; Alysha Bray; Jingwen Zhang; Ronald S. Reiserer; David K. Schaffer; Gregory B. Gerken; Clayton M. Britt; Erik M. Werner; Francis D. Gibbons; Tomasz Kostrzewski; Christopher E. Ch...; Emma J. Davies; Antonio Ramos Mon...; Jacqueline H. L. Fok; David Hughes; Kristin Fabre; Matthew P. Wagoner; John P. Wikswo; Clay W. Scott
• Keywords: In vitro toxicology

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) changes seen vivo and reduces predictive value of data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, Microformulator, which allows like PK profiles be applied cells cultured microtiter plates facilitates investigation impact biological responses. We demonstrate utility device its ability reproduce different oncology over multiweek experiments, both monotherapy drug combinations, comparing effects tumour efficacy with xenograft models. In first example, an ERK1/2 inhibitor was tested dosing Microformulator-replicated profiles, 2 lines sensitivities. The able discriminate between line sensitivities, unlike conventional dosing. second study, murine multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) DNA-dependent protein kinase (DNA-PK) combinations replicated FaDu resulting reduction growth similar rank ordering model. Additional PK/efficacy insight into theoretical exposure gained by Microformulator expose DNA-PK for target coverage levels periods time. that enables incorporating exposures cellular assays improve vitro–in translation understanding early therapeutic insight.