Animal-free assessment of developmental toxicity: Combining PBPK modeling with the ReproTracker assay

Marjory Moreau (a,*,1), Amer Jamalpoor (b,1,) John Carter Hall (a), Jeffrey Fisher (a), Sabine Hartvelt (b),

Giel Hendriks (b), Andy Nong (a), Todor Antonijevic (a)

(a) ScitoVation, LLC, Research Triangle Park, NC 27713, USA

(b) Toxys, Leiden Bioscience Park, Oegstgeest, the Netherlands

Abstract: in vitro screening platforms to assess teratogenic potential of compounds are emerging rapidly. ReproTracker is a

human induced pluripotent stem cells (hiPSCs)-based biomarker assay that is shown to identify the teratogenicity

potential of new pharmaceuticals and chemicals reliably. In its current state, the assay is limited to identifying

the potential teratogenic effects and does not immediately quantify a clinical dose relevant to the exposure of

chemicals or drugs observable in mothers or fetuses. The goal of this study was to evaluate whether the

ReproTracker assay can be extrapolated in vivo and quantitatively predict developmental toxicity exposure levels

of two known human teratogens, thalidomide, and carbamazepine. Here, we utilized Physiologically Based

Pharmacokinetic (PBPK) modeling to describe the pharmacokinetic behavior of these compounds and conducted

an in vitro to in vivo extrapolation (IVIVE) approach to predict human equivalent effect doses (HEDs) that

correspond with in vitro concentrations potentially associated with adverse outcomes in ReproTracker. The HEDs

derived from the ReproTracker concentration predicted to cause developmental toxicity were close to the reported

teratogenic human clinical doses and the HED derived from the rat or rabbit developmental toxicity study.

The ReproTracker derived-HED revealed to be sensitive and protective of humans. Overall, this pilot study

demonstrated the importance of integrating PBPK model in extrapolating and assessing developmental toxicity in

vitro. The combination of these tools demonstrated that they could improve the safety assessment of drugs and

chemicals without animal testing.

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