A Bespoke Microfluidic Method to Predict Drug Behaviour

Approximately 30% of drug candidates fail during animal testing because the pharmacokinetics could not be accurately predicted. Parallel Artificial Membrane Permeability Assay (PAMPA), a non cell-based assay, is currently a commonly used test to predict passive permeability of drugs in early drug discovery programs. With PAMPA in situ drug absorption occurs through phospholipid-doped plastic filters in 96-well plates. Lipid composition can be customized and pH in the donor and acceptor compartments on either side of the filter can be adjusted to mimic specific physiological conditions. 

However, there is concern regarding the disproportionate thickness of the plastic filter used, in comparison to the thickness of a cell membrane, as well as the presence of organic solvent in the interior of the phospholipid “membrane”. PAMPA predictions of drug absorption depend on bulk solutions which limit the ability to create customized, biomimetic pharmacokinetic compartments. There is need for a drug testing assay that can better mimic the pharmacokinetic pathway with respect to human physiology. This would provide valuable knowledge of how a drug truly acts in the human body as it moves, for example, from the intestine to the blood. This would increase the success rate of drugs progressing to clinical trials.

Researchers have generated a microfluidic platform to test pharmaceuticals or cosmetics without animal models, allowing for better prediction of pharmacokinetic parameters and the pathway a drug follows in the human body in a high throughput capacity. This platform uses pharmacokinetic compartments that consist of multiple droplets which are designed to model a desired compartment of the human body. For example, this model can be designed to mimic the path of a drug from the intestinal space into the blood via an enterocyte. The model uses at least two adjacent droplets (with the ability to employ more) with at least one phospholipid bilayer between them. There is an option of including one to eight barriers between the entry point and the targeted area of drug action. The model can be designed to follow various pathways with respect to human physiology and drug absorption. This method maintains the compartment method used in PAMPA, but replaces the thick, lipid filled membrane that pose concern with bespoke lipid mixtures that mimics those of human cells. Furthermore, this method preserves the differing rates of diffusion seen with different ionization states of a drug.

This bespoke microfluidic platform is innovative as, for the first time, droplet interface bilayers that mimic cell membrane breakdown have been created. This is helpful, for example, in tackling chemoresistance. Cancer causes cell membranes to break down, so mimicking this breakdown using artificial cells is critical for predicting pharmacokinetic parameters. These artificial cells were tested with doxorubicin, a chemotherapy, and successfully predicted its cell absorption. Thus, this technology has great potential to help explain and solve chemoresistance. In addition, the differences between female and male cell membranes can be mimicked, illuminating sex differences in drug behavior.

• In-vitro quantification of passive or active drug transport.
• Cancer drug discovery.
• Alzheimer drug discovery.