Human-on-a-Chip combined with PBPK modeling for in vitro/in vivo PK/PD extrapolation

Authors: Hickman J, Lukacova V
Software: GastroPlus®
Division: PBPK

Human-on-a-Chip (HoaC) systems are becoming valuable tools to study, understand disease physiology, and expand the prediction of pharmacodynamic effects before first-in-human studies. They can also be used to evaluate the toxic effects of compounds in non-pharma industries where these effects cannot be examined in vivo.

The utility of PBPK models has been demonstrated for:
– first-in-human PK predictions
– formulation optimization
– PK prediction in special populations
– drug-drug interaction predictions
– risk assessment of chemicals or consumer products (non-pharma)

The in vitro systems and experiments that are routinely used to parametrize the PBPK models are focused on a single property or process affecting the drug or chemical disposition in vivo and do not capture the secondary responses (e.g., the metabolite of A, made in the liver, circulates to another tissue causing the release of B which then causes other cells to change physiologically). A HoaC compensates for this lack of complete knowledge using cellular constructs that mimic the organ and allow organ-to-organ crosstalk due to the recirculating medium.

We’ll start with an overview of HoaC models, describing the various multi-organ systems that utilize a pumpless platform with a recirculating serum-free medium. The pumpless platform is a low volume system that enables evaluation of both parent and metabolite in the same model to allow PK and PD extrapolation of the results to in vivo systems. It will also describe the electrical and mechanical functional readouts for cardiac, skeletal muscle, neuronal and barrier tissues utilized in the system to enable not only acute but chronic compound evaluation for up to 28 days. Next, we’ll discuss potential applications of data obtained from the HoaC system to parameterize different aspects of the PBPK model for in vitro/in vivo extrapolation of PK and PD.

J. Hickman, Ph.D., Chief Scientist at Hesperos, and Viera Lukacova, Ph.D., Chief Scientist at Simulations Plus take questions at the end.

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