A PBPK-Compliant Human Intestine-Liver-Brain-Kidney Chip for Drug Development

Microphysiological systems (MPS) have proven to be a powerful tool for recreating human tissue- and organ-like functions. However, establishing complex human in vitro ADME models involving co-culture of key organs to mimic physiologically based pharmacokinetic (PBPK) distribution behavior still present a challenge. In our recent study, we developed a PBPK compliant ADME 4-Organ-Chip (Chip4) with a downscale factor of 1:100.000 of the human body. The integration of an intestinal barrier model for absorption and first-pass metabolism, liver microtissues for main metabolism, a kidney model with proximal tubular-like cells and podocytes for excretion, and neuronal spheroids as a potential target organ were optimized in the chip and co-cultured for 14 days. The setup was repeatedly exposed to Haloperidol, an antipsychotic medication and to Carbamazepine, a tricyclic compound with anticonvulsant properties through different routes. Results on direct as well as metabolite induced effects on organ-specific levels will be presented. Subsequently this data formed the basis for the development of an in silico PBPK model for compound prediction.

Learning Objectives:

1. Demonstrate ADME-on-a-chip.
2. Correlate selective drug transport.
3. Examine organ-specific toxicity.