Pharmacokinetic and pharmacodynamic insights from microfluidic intestine-on-a-chip models

ABSTRACT

Introduction: After administration, a drug undergoes absorption, distribution, metabolism, and elimination (ADME) before exerting its effect on the body. The combination of these process yields the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of a drug. Although accurate prediction of PK and PD profiles is essential for drug development, conventional in vitro models are limited by their lack of physiological relevance. Recently, microtechnology-based in vitro model systems, termed ‘organ-on-a-chip,’ have emerged as a potential solution.

Areas covered: Orally administered drugs are absorbed through the intestinal wall and transported to the liver before entering systemic circulation, which plays an important role in the PK and PD profiles. Recently developed, chip-based in vitro models can be useful models for simulating such processes and will be covered in this paper.

Expert opinion: The potential of intestine-on-a-chip models combined with conventional PK-PD modeling has been demonstrated with promising preliminary results. However, there are several challenges to overcome. Development of the intestinal wall, integration of the gut microbiome, and the provision of an intestine-specific environment must be achieved to realize in vivo-like intestinal model and enhance the efficiency of drug development.

KEYWORDS:

• Pharmacokinetics
• pharmacodynamics
• organ-on-a chip
• multi-organ-on-a-chip (MOC)
• intestine-on-a-chip
• gut-on-a-chip

Article highlights

• In the drug development process, pharmacokinetic (PK) and pharmacodynamic (PD) modeling are important for the prediction of drug response.

• Organ-on-a-chip technology has emerged as a novel in vitro methodology for simulating organ and tissue functions.

• Gut models that reproduce the physiological environment of the human gut, such as three-dimensional (3D) topology, dynamic environment, and gut-microbiome of an in vivo system, are introduced.

• Recent developments on the first-pass metabolism models that comprise the gut and liver compartments are summarized.

• Multi-organ models that include the gut and liver compartment with various target organs are introduced.

• The concept of PK and PD modeling, and how PK-PD models can be combined with multi-organ chip models are explained.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Ministry of Trade, Industry and Energy (MOTIE), Republic of Korea [10050154, Establishment of Infrastructure for industrialization of Korean Useful Microbes, R0004073] and Hongik University Research Fund. This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) [2018R1C1B5085757, 2019R1A4A102595811, and 2018M3C7A1056896] and the Ministry of Education [2018R1A6A1A03024231].