TY - JOUR
T1 - Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips
AU - Herland, Anna
AU - Maoz, Ben M.
AU - Das, Debarun
AU - Somayaji, Mahadevabharath R.
AU - Prantil-Baun, Rachelle
AU - Novak, Richard
AU - Cronce, Michael
AU - Huffstater, Tessa
AU - Jeanty, Sauveur S.F.
AU - Ingram, Miles
AU - Chalkiadaki, Angeliki
AU - Benson Chou, David
AU - Marquez, Susan
AU - Delahanty, Aaron
AU - Jalili-Firoozinezhad, Sasan
AU - Milton, Yuka
AU - Sontheimer-Phelps, Alexandra
AU - Swenor, Ben
AU - Levy, Oren
AU - Parker, Kevin K.
AU - Przekwas, Andrzej
AU - Ingber, Donald E.
N1 - Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans—using computationally scaled data from multiple fluidically linked two-channel organ chips—predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.
AB - Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans—using computationally scaled data from multiple fluidically linked two-channel organ chips—predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=85078415057&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41551-019-0498-9
DO - https://doi.org/10.1038/s41551-019-0498-9
M3 - Article
C2 - 31988459
SN - 2157-846X
VL - 4
SP - 421
EP - 436
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 4
ER -