Combination of a multi-organ microphysiological system (MO–MPS) and a
pharmacokinetic–pharmacodynamic (PK–PD) model to evaluate drug–drug
interactions (DDI)
Abstract
In the field of drug discovery, the emergence of unexpected toxicity is
often a problem resulting from a poor understanding of the
pharmacokinetics of drug–drug interactions (DDI). In this context,
“organs-on-a-chip” has been proposed as a novel in vitro model to
evaluate drug efficacy and toxicity in pharmacology, but it has not yet
been applied to DDI research. Here, we aim to first estimate a
drug-specific parameter, namely, extraction ratio, using a multi-organ
microphysiological system (MO–MPS) and to subsequently evaluate the DDI
using a pharmacokinetic–pharmacodynamic (PK–PD) model. For this, we
propose a combination of an MO–MPS, with a liver part as a metabolic
model and a cancer part as a drug target model, and its corresponding
PK–PD model. The results of the DDI effects evaluated, thus, were
consistent with those previously reported, confirming the efficacy of
the combination of an MPS and a PK–PD model in DDI research. It is
possible to evaluate more clearly, the effect of the concomitantly
administered drugs on the pharmacokinetic changes occurring in MPS, by
evaluating DDI by the PK–PD model, using parameters inferred from the
experimental results. Our proposed method could facilitate both, a
better understanding of the pharmacokinetic mechanisms with DDI as also
the evaluation of organ–organ interactions using multi-organ MPS.