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Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.

ABSTRACT: Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model-aided drug development. While the need for a functional design considering organ-organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into the current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in the different stages of PBPK modeling and drug development; these are ?Organs-on-a-chip and ?Human-on-a-chip. Then we establish the design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations for estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on the design of microphysiological platforms for PBPK/PD based drug discovery.

SUBMITTER: Abaci HE

PROVIDER: S-EPMC4407827 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.

Abaci Hasan Erbil HE Shuler Michael L ML

Integrative biology : quantitative biosciences from nano to macro 20150401 4

Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model-aided drug development. While the need for a functional design considering organ-organ interactions has ...[more]

PMID: 25739725

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Project description:Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models can serve as a powerful framework for predicting the influence as well as the interaction of formulation, genetic polymorphism and co-medication on the pharmacokinetics and pharmacodynamics of drug substances. In this study, flurbiprofen, a potent non-steroid anti-inflammatory drug, was chosen as a model drug. Flurbiprofen has absolute bioavailability of ~95% and linear pharmacokinetics in the dose range of 50-300 mg. Its absorption is considered variable and complex, often associated with double peak phenomena, and its pharmacokinetics are characterized by high inter-subject variability, mainly due to its metabolism by the polymorphic CYP2C9 (fmCYP2C9 ? 0.71). In this study, by leveraging in vitro, in silico and in vivo data, an integrated PBPK/PD model with mechanistic absorption was developed and evaluated against clinical data from PK, PD, drug-drug and gene-drug interaction studies. The PBPK model successfully predicted (within 2-fold) 36 out of 38 observed concentration-time profiles of flurbiprofen as well as the CYP2C9 genetic effects after administration of different intravenous and oral dosage forms over a dose range of 40-300 mg in both Caucasian and Chinese healthy volunteers. All model predictions for Cmax, AUCinf and CL/F were within two-fold of their respective mean or geometric mean values, while 90% of the predictions of Cmax, 81% of the predictions of AUCinf and 74% of the predictions of Cl/F were within 1.25 fold. In addition, the drug-drug and drug-gene interactions were predicted within 1.5-fold of the observed interaction ratios (AUC, Cmax ratios). The validated PBPK model was further expanded by linking it to an inhibitory Emax model describing the analgesic efficacy of flurbiprofen and applying it to explore the effect of formulation and genetic polymorphisms on the onset and duration of pain relief. This comprehensive PBPK/PD analysis, along with a detailed translational biopharmaceutic framework including appropriately designed biorelevant in vitro experiments and in vitro-in vivo extrapolation, provided mechanistic insight on the impact of formulation and genetic variations, two major determinants of the population variability, on the PK/PD of flurbiprofen. Clinically relevant specifications and potential dose adjustments were also proposed. Overall, the present work highlights the value of a translational PBPK/PD approach, tailored to target populations and genotypes, as an approach towards achieving personalized medicine.

Dataset Information

Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.

Publications

Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.

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