The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development

Abstract

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

Keywords: human-induced pluripotent stem cells; in vitro to in vivo translation; microphysiological systems; organoid; pharmacokinetic/pharmacodynamic model; physiologically based pharmacokinetic model; quantitative systems pharmacology model.

Figure 1

A brief history of the development of in vitro tools. iPSC: induced pluripotent stem cells [18,19,20,21,22,23,24,25].

Figure 2

The current various in vitro tools. (a) 2D cell culture. (b) 3D cell culture. (c) hiPSC culture process. Somatic cells are extracted from healthy people or patients and converted into hiPSC through reprogramming. The obtained cells can be differentiated into other cells, such as cardiomyocytes, neurons cells, and endothelial cells. (d) Organoid culture process. Organoids can be cultured from human-derived single cell, homogeneous multicellular ensemble, and heterogeneous coculture of different cell types through self-organization. (e) Microphysiological systems: (1) controllable and programmable microfluidic cell culture system; (2) structure of organ-on-chips; and (3) integration of or-gan-on-chips, body-on-chips. hiPSC: human-induced pluripotent stem cell.

Figure 3

The progress of in vitro to in vivo translation. It is a bottom-up research method. Through high-quality in vitro experimental data and mathematical models, more accurate predictions of in vivo outcome can be obtained. PBPK: physiologically based pharmacokinetic model; PK/PD: pharmacokinetic/pharmacodynamic model; QSP: quantitative systems pharmacology model; MPS: microphysiological system; hiPSC: human-induced pluripotent stem cell.